Molecules


Residue numbers, where applicable, are given for rat proteins.
The ligand is DNP-BSA and is taken to have two virtual haptens.
Each hapten has two possible states, buried (b) or exposed (e).

Lig(hap~b~e,hap~b~e)

Lig hap b e hap b e

The receptor is a complex of FceRI and an IgE antibody.
The "fab" components represent the two fab arms of hapten-specific IgE.
b_Y218 and b_Y224 are tyrosines in the ITAM of the beta subunit.
b_Y224 is non-canonical, located between the two canonical tyrosines of the ITAM.
Y65 and Y76 are tyrosines in the ITAM of the gamma subunit and are lumped as a single site.
Only one (of the two) gamma chains is considered, as a simplification.

Rec(fab,fab,b_Y218~0~P,b_Y224~0~P,g_Y65_Y76~0~P)

Rec fab fab b_Y218 0 P b_Y224 0 P g_Y65_Y76 0 P

Lyn is an SFK with a unique domain (U), an SH2 domain, and an SH3 domain.
Y397 is located in the kinase activation loop, and Y508 is the inhibitory C-terminal tyrosine.

Lyn(U,SH3,SH2,Y397~0~P,Y508~0~P)

Lyn U SH3 SH2 Y397 0 P Y508 0 P

Fyn is an SFK with a unique domain (U), an SH2 domain, and an SH3 domain.
Y420 is located in the kinase activation loop, and Y531 is the inhibitory C-terminal tyrosine.

Fyn(U,SH3,SH2,PTK,Y420~0~P,Y531~0~P)

Fyn U SH3 SH2 PTK Y420 0 P Y531 0 P

Syk is a kinase with tandem SH2 domains, which are lumped as a single site.
Y346 is located in Interdomain B.
Y519 and Y520 are located in the activation loop of the kinase domain. These tyrosines are lumped as a single site.

Syk(tSH2,Y346~0~P,PTK,Y519_Y520~0~P)

Syk tSH2 Y346 0 P PTK Y519_Y520 0 P

Pag1 is an adaptor protein with two proline-rich sequences (PRS1 and PRS2) and multiple phosphosites.
Y165 and Y183 are lumped as a single site, as are Y386 and Y409.
PRS1 represents the PRIP motif starting at P136.
PRS2 represents the PPVP motif starting at P255.

Pag1(PRS1,Y165_Y183~0~P,PRS2,Y317~0~P,Y386_Y409~0~P)

Pag1 PRS1 Y165_Y183 0 P PRS2 Y317 0 P Y386_Y409 0 P

Csk is a kinase with an SH2 domain.

Csk(SH2)

Csk SH2

Lat is an adaptor protein with multiple tyrosine residues that undergo phosphorylation, of which we focus on Y136 and Y175

Lat(Y136~0~P,Y175~0~P)

Lat Y136 0 P Y175 0 P

Phospholipase C gamma 1 (Plcg1)

Plcg1(SH2,SH3,PLC,Y783~0~P)

Plcg1 SH2 SH3 PLC Y783 0 P

Grb2 is an adaptor protein with an SH2 domain and two SH3 domains, of which we consider the C-terminal domain.

Grb2(SH2,cSH3)

Grb2 SH2 cSH3

Gab2 is an adaptor protein

Gab2(PRS,Y441~0~P)

Gab2 PRS Y441 0 P

Grap2 is an adaptor protein

Grap2(SH2,SH3)

Grap2 SH2 SH3

Lcp2 is an adaptor protein

Lcp2(RxxK,PRS)

Lcp2 RxxK PRS

PI 3-kinase is a heterodimeric lipid kinase that can phosphorylate the 3 position of an inositol ring.
Its p85 subunit contains an SH2 domain.

Pi3k(p85_SH2,PI3Kc)

Pi3k p85_SH2 PI3Kc

Btk is a Tec family kinase

Btk(PH,PTK)

Btk PH PTK

Inpp5d is an inositol phosphatase. It is also known as Ship1.
It contains an SH2 domain, a C2 domain that can bind lipid species, and an inositol polyphosphate phosphatase catalytic domain (IPP)

Inpp5d(SH2,IPP,C2)

Inpp5d SH2 IPP C2

Phosphatidylinositol 3,4-bisphosphate, or PtdIns(3,4)P2, is a phospholipid.
The "bind" component is a virtual site for protein interactions.

PI34P2(bind)

PI34P2 bind

Phosphatidylinositol 4,5-bisphosphate, or PtdIns(4,5)P2, is a phospholipid.
The "bind" component is a virtual site for protein interactions.

PI45P2(bind)

PI45P2 bind

Phosphatidylinositol 3,4,5-trisphosphate, or PtdIns(3,4,5)P3, is a phospholipid.
The "bind" component is a virtual site for protein interactions.

PI345P3(bind)

PI345P3 bind

Inositol 1,4,5-trisphosphate

IP3()

IP3

Diacyl glycerol

DAG()

DAG

Sink

Sink()

Sink

PI4P()

PI4P

Species

Lig(hap~b,hap~b)

Lig hap b hap b

Rec(fab,fab,b_Y218~0,b_Y224~0,g_Y65_Y76~0)

Rec fab fab b_Y218 0 b_Y224 0 g_Y65_Y76 0

Lyn(U,SH2,SH3,Y397~0,Y508~0)

Lyn U SH2 SH3 Y397 0 Y508 0

Fyn(U,SH2,SH3,Y420~0,PTK,Y531~0)

Fyn U SH2 SH3 Y420 0 PTK Y531 0

Syk(tSH2,Y346~0,PTK,Y519_Y520~0)

Syk tSH2 Y346 0 PTK Y519_Y520 0

Pag1(PRS1,PRS2,Y317~0,Y165_Y183~0,Y386_Y409~0)

Pag1 PRS1 PRS2 Y317 0 Y165_Y183 0 Y386_Y409 0

Csk(SH2)

Csk SH2

Lat(Y136~0,Y175~0)

Lat Y136 0 Y175 0

Plcg1(SH2,SH3,PLC,Y783~0)

Plcg1 SH2 SH3 PLC Y783 0

Grb2(SH2,cSH3)

Grb2 SH2 cSH3

Gab2(PRS,Y441~0)

Gab2 PRS Y441 0

PI45P2(bind)

PI45P2 bind

Pi3k(PI3Kc,p85_SH2)

Pi3k PI3Kc p85_SH2

Btk(PH,PTK)

Btk PH PTK

Inpp5d(SH2,C2,IPP)

Inpp5d SH2 C2 IPP

Grap2(SH2,SH3)

Grap2 SH2 SH3

Lcp2(RxxK,PRS)

Lcp2 RxxK PRS

PI4P()

PI4P

Sink()

Sink

Observables

Lat_pY136 Lat(Y136~P!?)

Lat Y136 ?P Y175 0 ?P

Lat_pY175 Lat(Y175~P!?)

Lat Y136 0 ?P Y175 ?P

Rec_pY218 Rec(b_Y218~P!?)

Rec ?fab ?fab b_Y218 ?P b_Y224 0 ?P g_Y65_Y76 0 ?P

Rec_pY224 Rec(b_Y224~P!?)

Rec ?fab ?fab b_Y218 0 ?P b_Y224 ?P g_Y65_Y76 0 ?P

Rec_pY65_Y76 Rec(g_Y65_Y76~P!?)

Rec ?fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 ?P

Syk_pY346 Syk(Y346~P!?)

Syk ?tSH2 Y346 ?P ?PTK Y519_Y520 0 ?P

Gab2_pY441 Gab2(Y441~P!?)

Gab2 ?PRS Y441 ?P

PI3K_recruited Lat(Y175~P!1).Grb2(SH2!1,cSH3!2).Gab2(PRS!2,Y441~P!3).Pi3k(p85_SH2!3)

Lat Y136 0 ?P Y175 P Grb2 SH2 cSH3 Gab2 PRS Y441 P Pi3k p85_SH2 ?PI3Kc

PI345P3 PI345P3(bind!?)

PI345P3 ?bind

Plcg1_pY783 Plcg1(Y783~P!?)

Plcg1 ?SH2 ?SH3 ?PLC Y783 ?P

LynUbound Lyn(U!+)

Lyn U ?SH3 ?SH2 Y397 0 ?P Y508 0 ?P

LynSH2bound Lyn(SH2!+)

Lyn ?U ?SH3 SH2 Y397 0 ?P Y508 0 ?P

Shipbound Inpp5d(SH2!+)

Inpp5d SH2 ?IPP ?C2

Plc_pip2 Plcg1(PLC!1).PI45P2(bind!1)

Plcg1 ?SH2 ?SH3 PLC Y783 0 ?P PI45P2 bind

Lat_Plc Lat(Y136~P!1).Plcg1(SH2!1)

Lat Y136 P Y175 0 ?P Plcg1 SH2 ?SH3 ?PLC Y783 0 ?P

IP3 IP3()

IP3

PI34P2 PI34P2(bind!?)

PI34P2 ?bind

PI45P2 PI45P2(bind!?)

PI45P2 ?bind

Pag_Y165 Pag1(Y165_Y183~P!?)

Pag1 ?PRS1 Y165_Y183 ?P ?PRS2 Y317 0 ?P Y386_Y409 0 ?P

Pag_Y409 Pag1(Y386_Y409~P!?)

Pag1 ?PRS1 Y165_Y183 0 ?P ?PRS2 Y317 0 ?P Y386_Y409 ?P

LynIn Lyn(SH2!1,Y508~P!1)

Lyn ?U ?SH3 SH2 Y397 0 ?P Y508 P

FynIn Fyn(SH2!1,Y531~P!1)

Fyn ?U ?SH3 SH2 ?PTK Y420 0 ?P Y531 P

Lyn_pY508 Lyn(Y508~P!?)

Lyn ?U ?SH3 ?SH2 Y397 0 ?P Y508 ?P

Fyn_pY508 Fyn(Y531~P!?)

Fyn ?U ?SH3 ?SH2 ?PTK Y420 0 ?P Y531 ?P

Btk_recruited Btk(PH!+)

Btk PH ?PTK

Free ligand

LigFree Lig(hap,hap)

Lig hap hap

Crosslinked receptor dimer

Crosslinks Lig(hap~e!1,hap~e!2).Rec(fab!1).Rec(fab!2)

Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 0 ?P Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 0 ?P

Ligand with both haptens buried

DNP_exposed_0_of_2 Lig(hap~b!?,hap~b!?)

Lig hap ?b hap ?b

Ligand with one hapten exposed

DNP_exposed_1_of_2 Lig(hap~b!?,hap~e!?)

Lig hap ?b hap ?e

Ligand with both haptens exposed

DNP_exposed_2_of_2 Lig(hap~e!?,hap~e!?)

Lig hap ?e hap ?e

Total ligand

LigTotal Lig(hap!?,hap!?)

Lig ?hap ?hap

Syk_pY519_520 Syk(Y519_Y520~P)

Syk ?tSH2 Y346 0 ?P ?PTK Y519_Y520 P

Reaction Rules


Haptens are transiently exposed.

Lig(hap~b) <-> Lig(hap~e)

Lig hap b e take all branches, once each, in any order⬇⬆ hap b ?e

Binding from solution when a hapten is exposed. Does not depend on state of second hapten.

Lig(hap~e,hap~e) + Rec(fab) -> Lig(hap~e,hap~e!1).Rec(fab!1)

Lig hap e hap ⬇e ⬇ Rec ⬇fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 0 ?P

Lig(hap~b,hap~e) + Rec(fab) -> Lig(hap~b,hap~e!1).Rec(fab!1)

Lig hap b hap ⬇e ⬇ Rec ⬇fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 0 ?P

Receptor crosslinking when both haptens are exposed.

Lig(hap~e,hap~e!1).Rec(fab!1) + Rec(fab) -> Lig(hap~e!2,hap~e!1).Rec(fab!1).Rec(fab!2)

Lig hap ⬇e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 0 ?P ⬇ Rec ⬇fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 0 ?P

Dissociation of hapten from receptor site

Lig(hap~e!1).Rec(fab!1) -> Lig(hap~e) + Rec(fab)

Lig hap ⬆e hap b ?e ⬆ Rec ⬆fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 0 ?P

Lyn unique domain binds receptor

Rec(b_Y218~0) + Lyn(U,SH3,SH2) -> Rec(b_Y218~0!1).Lyn(U!1,SH3,SH2)

Rec ?fab ?fab b_Y218 ⬇0 b_Y224 0 ?P g_Y65_Y76 0 ?P ⬇ Lyn ⬇U SH3 SH2 Y397 0 ?P Y508 0 ?P

Lyn unique domain dissociates from receptor

Rec(b_Y218~0!1).Lyn(U!1) -> Rec(b_Y218~0) + Lyn(U)

Rec ?fab ?fab b_Y218 ⬆0 b_Y224 0 ?P g_Y65_Y76 0 ?P ⬆ Lyn ⬆U ?SH3 ?SH2 Y397 0 ?P Y508 0 ?P

Lyn SH2 domain binds receptor

Rec(b_Y218~P) + Lyn(U,SH3,SH2) -> Rec(b_Y218~P!1).Lyn(U,SH3,SH2!1)

Rec ?fab ?fab b_Y218 ⬇P b_Y224 0 ?P g_Y65_Y76 0 ?P ⬇ Lyn U SH3 ⬇SH2 Y397 0 ?P Y508 0 ?P

Lyn SH2 domain dissociates from receptor

Rec(b_Y218~P!1).Lyn(SH2!1) -> Rec(b_Y218~P) + Lyn(SH2)

Rec ?fab ?fab b_Y218 ⬆P b_Y224 0 ?P g_Y65_Y76 0 ?P ⬆ Lyn ?U ?SH3 ⬆SH2 Y397 0 ?P Y508 0 ?P

Lyn SH2 domain binds Lyn pY508, forming an intramolecular bond

Lyn(U,SH3,SH2,Y508~P) -> Lyn(U,SH3,SH2!1,Y508~P!1)

Lyn U SH3 ⬇SH2 Y397 0 ?P Y508 ⬇P

Lyn SH2 dissociates from Lyn pY508

Lyn(SH2!1,Y508~P!1) -> Lyn(SH2,Y508~P)

Lyn ?U ?SH3 ⬆SH2 Y397 0 ?P Y508 ⬆P

# Lyn phosphorylates Y218 in the beta subunit of the receptor.
Lyn bound by its unqiue domain

Lyn(U!1).Rec(b_Y218~0!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y218~0) -> Lyn(U!1).Rec(b_Y218~0!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y218~P)

Lyn U ?SH3 ?SH2 Y397 0 ?P Y508 0 ?P Rec fab ?fab b_Y218 0 b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 P take all branches, once each, in any order⬇ b_Y224 0 ?P g_Y65_Y76 0 ?P

Lyn bound by its SH2 domain

Lyn(SH2!1).Rec(b_Y218~P!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y218~0) -> Lyn(SH2!1).Rec(b_Y218~P!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y218~P)

Lyn ?U ?SH3 SH2 Y397 0 ?P Y508 0 ?P Rec fab ?fab b_Y218 P b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 P take all branches, once each, in any order⬇ b_Y224 0 ?P g_Y65_Y76 0 ?P

# Lyn phosphorylates Y224 in the beta subunit of the receptor.
Lyn bound by its unqiue domain

Lyn(U!1).Rec(b_Y218~0!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y224~0) -> Lyn(U!1).Rec(b_Y218~0!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y224~P)

Lyn U ?SH3 ?SH2 Y397 0 ?P Y508 0 ?P Rec fab ?fab b_Y218 0 b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 P take all branches, once each, in any order⬇ g_Y65_Y76 0 ?P

Lyn bound by its SH2 domain

Lyn(SH2!1).Rec(b_Y218~P!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y224~0) -> Lyn(SH2!1).Rec(b_Y218~P!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y224~P)

Lyn ?U ?SH3 SH2 Y397 0 ?P Y508 0 ?P Rec fab ?fab b_Y218 P b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 P take all branches, once each, in any order⬇ g_Y65_Y76 0 ?P

# Lyn phosphorylates Y65 and Y76 in the gamma subunit of the receptor.
Lyn bound by its unqiue domain

Lyn(U!1).Rec(b_Y218~0!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~0) -> Lyn(U!1).Rec(b_Y218~0!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P)

Lyn U ?SH3 ?SH2 Y397 0 ?P Y508 0 ?P Rec fab ?fab b_Y218 0 b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 0 P take all branches, once each, in any order⬇

Lyn bound by its SH2 domain

Lyn(SH2!1).Rec(b_Y218~P!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~0) -> Lyn(SH2!1).Rec(b_Y218~P!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P)

Lyn ?U ?SH3 SH2 Y397 0 ?P Y508 0 ?P Rec fab ?fab b_Y218 P b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 0 P take all branches, once each, in any order⬇

Syk binds the dually phosphorylated gamma subunit of the receptor

Syk(tSH2) + Rec(g_Y65_Y76~P) <-> Syk(tSH2!1).Rec(g_Y65_Y76~P!1)

Syk ⬇⬆tSH2 Y346 0 ?P ?PTK Y519_Y520 0 ?P ⬇⬆ Rec ?fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 ⬇⬆P

# Lyn phosphorylates Syk
Lyn bound by its unique domain

Lyn(U!1).Rec(fab!2,b_Y218~0!1).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P!4).Syk(tSH2!4,Y346~0) -> Lyn(U!1).Rec(fab!2,b_Y218~0!1).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P!4).Syk(tSH2!4,Y346~P)

Lyn U ?SH3 ?SH2 Y397 0 ?P Y508 0 ?P Rec fab ?fab b_Y218 0 b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 P Syk tSH2 Y346 0 P take all branches, once each, in any order⬇ ?PTK Y519_Y520 0 ?P

Lyn bound by its SH2 domain

Lyn(SH2!1).Rec(fab!2,b_Y218~P!1).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P!4).Syk(tSH2!4,Y346~0) -> Lyn(SH2!1).Rec(fab!2,b_Y218~P!1).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P!4).Syk(tSH2!4,Y346~P)

Lyn ?U ?SH3 SH2 Y397 0 ?P Y508 0 ?P Rec fab ?fab b_Y218 P b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 P Syk tSH2 Y346 0 P take all branches, once each, in any order⬇ ?PTK Y519_Y520 0 ?P

# Syk trans-phosphorylates the activation loop tyrosine of another Syk molecule
Syk unphosphorlyated on activation loop

Syk(tSH2!1,Y519_Y520~0).Rec(fab!2,g_Y65_Y76~P!1).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P!4).Syk(tSH2!4,Y519_Y520~0) -> Syk(tSH2!1,Y519_Y520~0).Rec(fab!2,g_Y65_Y76~P!1).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P!4).Syk(tSH2!4,Y519_Y520~P)

Syk tSH2 Y346 0 ?P ?PTK Y519_Y520 0 Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 P Syk tSH2 Y346 0 ?P ?PTK Y519_Y520 0 P take all branches, once each, in any order⬇

Syk phosphorylated on activation loop

Syk(tSH2!1,Y519_Y520~P).Rec(fab!2,g_Y65_Y76~P!1).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P!4).Syk(tSH2!4,Y519_Y520~0) -> Syk(tSH2!1,Y519_Y520~P).Rec(fab!2,g_Y65_Y76~P!1).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P!4).Syk(tSH2!4,Y519_Y520~P)

Syk tSH2 Y346 0 ?P ?PTK Y519_Y520 P Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 P Syk tSH2 Y346 0 ?P ?PTK Y519_Y520 0 P take all branches, once each, in any order⬇

# SH3 domain of Lyn binds PRS2 in Pag1
Association when Lyn is free

Lyn(U,SH3,SH2) + Pag1(PRS2,Y386_Y409) -> Lyn(U,SH3!1,SH2).Pag1(PRS2!1,Y386_Y409)

Lyn U ⬇SH3 SH2 Y397 0 ?P Y508 0 ?P ⬇ Pag1 ?PRS1 Y165_Y183 0 ?P ⬇PRS2 Y317 0 ?P Y386_Y409

Association when Lyn is tethered to Pag1 by an SH2 domain-pY interaction
Lyn, already tethered in Pag1 by SH2, binds Pag1 via SH3 domain

Lyn(U,SH3,SH2!2).Pag1(PRS2,Y386_Y409~P!2) -> Lyn(U,SH3!1,SH2!2).Pag1(PRS2!1,Y386_Y409~P!2)

Lyn U ⬇SH3 SH2 Y397 0 ?P Y508 0 ?P Pag1 ?PRS1 Y165_Y183 0 ?P ⬇PRS2 Y317 0 ?P Y386_Y409 P

Dissociation of Lyn SH3

Lyn(SH3!1,SH2).Pag1(PRS2!1,Y386_Y409) -> Lyn(SH3,SH2) + Pag1(PRS2,Y386_Y409)

Lyn ?U ⬆SH3 SH2 Y397 0 ?P Y508 0 ?P ⬆ Pag1 ?PRS1 Y165_Y183 0 ?P ⬆PRS2 Y317 0 ?P Y386_Y409

SH2 domain of Lyn binds a pY docking site in Pag1
Association when Lyn is free

Lyn(U,SH3,SH2) + Pag1(PRS2,Y386_Y409~P) -> Lyn(U,SH3,SH2!2).Pag1(PRS2,Y386_Y409~P!2)

Lyn U SH3 ⬇SH2 Y397 0 ?P Y508 0 ?P ⬇ Pag1 ?PRS1 Y165_Y183 0 ?P PRS2 Y317 0 ?P Y386_Y409 ⬇P

Association when Lyn is tethered to Pag1 via an SH3 domain-PRS interaction

Lyn(U,SH3!1,SH2).Pag1(PRS2!1,Y386_Y409~P) -> Lyn(U,SH3!1,SH2!2).Pag1(PRS2!1,Y386_Y409~P!2)

Lyn U SH3 ⬇SH2 Y397 0 ?P Y508 0 ?P Pag1 ?PRS1 Y165_Y183 0 ?P PRS2 Y317 0 ?P Y386_Y409 ⬇P

Dissociation of Lyn from Pag1, breaking two-point attachment
Because association of the Lyn SH3 domain with Pag1 PRS2 is rapid (relative to the lifetime of a pY-SH2 bond) when Lyn is tethered by its SH2 domain,
we omit dissociation of the SH2 domain alone, as a simplification.

Lyn(SH3!1,SH2!2).Pag1(PRS2!1,Y386_Y409~P!2) -> Lyn(SH3,SH2) + Pag1(PRS2,Y386_Y409~P)

Lyn ?U ⬆SH3 ⬆SH2 Y397 0 ?P Y508 0 ?P ⬆ Pag1 ?PRS1 Y165_Y183 0 ?P ⬆PRS2 Y317 0 ?P Y386_Y409 ⬆P

Lyn phosphorylates Y386 and Y409 in Pag1

Lyn(SH3!1,Y508).Pag1(PRS2!1,Y386_Y409~0) -> Lyn(SH3!1,Y508).Pag1(PRS2!1,Y386_Y409~P)

Lyn ?U SH3 ?SH2 Y397 0 ?P Y508 Pag1 ?PRS1 Y165_Y183 0 ?P PRS2 Y317 0 ?P Y386_Y409 0 P take all branches, once each, in any order⬇

Lyn phosphorylates Y165 and Y183 in Pag1

Lyn(SH3,SH2!1,Y508).Pag1(Y165_Y183~0,Y386_Y409~P!1) -> Lyn(SH3,SH2!1,Y508).Pag1(Y165_Y183~P,Y386_Y409~P!1)

Lyn ?U SH3 SH2 Y397 0 ?P Y508 Pag1 ?PRS1 Y165_Y183 0 P take all branches, once each, in any order⬇ ?PRS2 Y317 0 ?P Y386_Y409 P

Lyn(SH3!2,SH2!1,Y508).Pag1(PRS2!2,Y165_Y183~0,Y386_Y409~P!1) -> Lyn(SH3!2,SH2!1,Y508).Pag1(PRS2!2,Y165_Y183~P,Y386_Y409~P!1)

Lyn ?U SH3 SH2 Y397 0 ?P Y508 Pag1 ?PRS1 Y165_Y183 0 P take all branches, once each, in any order⬇ PRS2 Y317 0 ?P Y386_Y409 P

Lyn(SH3!1,SH2,Y508).Pag1(PRS2!1,Y165_Y183~0) -> Lyn(SH3!1,SH2,Y508).Pag1(PRS2!1,Y165_Y183~P)

Lyn ?U SH3 SH2 Y397 0 ?P Y508 Pag1 ?PRS1 Y165_Y183 0 P take all branches, once each, in any order⬇ PRS2 Y317 0 ?P Y386_Y409 0 ?P

Lyn(SH2!1,Y508).Pag1(Y317~0,Y386_Y409~P!1) -> Lyn(SH2!1,Y508).Pag1(Y317~P,Y386_Y409~P!1)

Lyn ?U ?SH3 SH2 Y397 0 ?P Y508 Pag1 ?PRS1 Y165_Y183 0 ?P ?PRS2 Y317 0 P take all branches, once each, in any order⬇ Y386_Y409 P

Lyn phosphorylates Y317 in Pag1

Lyn(SH3,SH2!1,Y508).Pag1(Y317~0,Y386_Y409~P!1) -> Lyn(SH3,SH2!1,Y508).Pag1(Y317~P,Y386_Y409~P!1)

Lyn ?U SH3 SH2 Y397 0 ?P Y508 Pag1 ?PRS1 Y165_Y183 0 ?P ?PRS2 Y317 0 P take all branches, once each, in any order⬇ Y386_Y409 P

Lyn(SH3!2,SH2!1,Y508).Pag1(PRS2!2,Y317~0,Y386_Y409~P!1) -> Lyn(SH3!2,SH2!1,Y508).Pag1(PRS2!2,Y317~P,Y386_Y409~P!1)

Lyn ?U SH3 SH2 Y397 0 ?P Y508 Pag1 ?PRS1 Y165_Y183 0 ?P PRS2 Y317 0 P take all branches, once each, in any order⬇ Y386_Y409 P

Lyn(SH3!1,SH2,Y508).Pag1(PRS2!1,Y317~0) -> Lyn(SH3!1,SH2,Y508).Pag1(PRS2!1,Y317~P)

Lyn ?U SH3 SH2 Y397 0 ?P Y508 Pag1 ?PRS1 Y165_Y183 0 ?P PRS2 Y317 0 P take all branches, once each, in any order⬇ Y386_Y409 0 ?P

SH2 domain of Csk binds pY317 docking site in Pag1

Csk(SH2) + Pag1(Y317~P) <-> Csk(SH2!3).Pag1(Y317~P!3)

Csk ⬇⬆SH2 ⬇⬆ Pag1 ?PRS1 Y165_Y183 0 ?P ?PRS2 Y317 ⬇⬆P Y386_Y409 0 ?P

Csk cis phosphorylates Y508 in Lyn

Lyn(SH3,SH2!1,Y508~0).Pag1(Y386_Y409~P!1,Y317~P!2).Csk(SH2!2) -> Lyn(SH3,SH2!1,Y508~P).Pag1(Y386_Y409~P!1,Y317~P!2).Csk(SH2!2)

Lyn ?U SH3 SH2 Y397 0 ?P Y508 0 P take all branches, once each, in any order⬇ Pag1 ?PRS1 Y165_Y183 0 ?P ?PRS2 Y317 P Y386_Y409 P Csk SH2

Lyn(SH3!1,SH2,Y508~0).Pag1(PRS2!1,Y317~P!2).Csk(SH2!2) -> Lyn(SH3!1,SH2,Y508~P).Pag1(PRS2!1,Y317~P!2).Csk(SH2!2)

Lyn ?U SH3 SH2 Y397 0 ?P Y508 0 P take all branches, once each, in any order⬇ Pag1 ?PRS1 Y165_Y183 0 ?P PRS2 Y317 P Y386_Y409 0 ?P Csk SH2

Lyn(SH3!1,SH2!3,Y508~0).Pag1(PRS2!1,Y386_Y409~P!3,Y317~P!2).Csk(SH2!2) -> Lyn(SH3!1,SH2!3,Y508~P).Pag1(PRS2!1,Y386_Y409~P!3,Y317~P!2).Csk(SH2!2)

Lyn ?U SH3 SH2 Y397 0 ?P Y508 0 P take all branches, once each, in any order⬇ Pag1 ?PRS1 Y165_Y183 0 ?P PRS2 Y317 P Y386_Y409 P Csk SH2

Fyn unique domain binds receptor

Rec(b_Y218~0) + Fyn(U,SH3,SH2) -> Rec(b_Y218~0!1).Fyn(U!1,SH3,SH2)

Rec ?fab ?fab b_Y218 ⬇0 b_Y224 0 ?P g_Y65_Y76 0 ?P ⬇ Fyn ⬇U SH3 SH2 ?PTK Y420 0 ?P Y531 0 ?P

Fyn unique domain dissociates from receptor

Rec(b_Y218~0!1).Fyn(U!1) -> Rec(b_Y218~0) + Fyn(U)

Rec ?fab ?fab b_Y218 ⬆0 b_Y224 0 ?P g_Y65_Y76 0 ?P ⬆ Fyn ⬆U ?SH3 ?SH2 ?PTK Y420 0 ?P Y531 0 ?P

Fyn SH2 domain binds receptor

Rec(b_Y218~P) + Fyn(U,SH3,SH2) -> Rec(b_Y218~P!1).Fyn(U,SH3,SH2!1)

Rec ?fab ?fab b_Y218 ⬇P b_Y224 0 ?P g_Y65_Y76 0 ?P ⬇ Fyn U SH3 ⬇SH2 ?PTK Y420 0 ?P Y531 0 ?P

Fyn SH2 domain dissociates from receptor

Rec(b_Y218~P!1).Fyn(SH2!1) -> Rec(b_Y218~P) + Fyn(SH2)

Rec ?fab ?fab b_Y218 ⬆P b_Y224 0 ?P g_Y65_Y76 0 ?P ⬆ Fyn ?U ?SH3 ⬆SH2 ?PTK Y420 0 ?P Y531 0 ?P

Fyn SH2 domain binds Fyn pY531, forming an intramolecular bond

Fyn(U,SH3,SH2,Y531~P) -> Fyn(U,SH3,SH2!1,Y531~P!1)

Fyn U SH3 ⬇SH2 ?PTK Y420 0 ?P Y531 ⬇P

Fyn SH2 domain dissociates from pY531

Fyn(SH2!1,Y531~P!1) -> Fyn(SH2,Y531~P)

Fyn ?U ?SH3 ⬆SH2 ?PTK Y420 0 ?P Y531 ⬆P

Fyn phosphorylates Y218 in the beta subunit of the receptor
Fyn bound by its unique domain

Fyn(U!1).Rec(b_Y218~0!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y218~0) -> Fyn(U!1).Rec(b_Y218~0!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y218~P)

Fyn U ?SH3 ?SH2 ?PTK Y420 0 ?P Y531 0 ?P Rec fab ?fab b_Y218 0 b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 P take all branches, once each, in any order⬇ b_Y224 0 ?P g_Y65_Y76 0 ?P

Fyn bound by its SH2 domain

Fyn(SH2!1).Rec(b_Y218~P!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y218~0) -> Fyn(SH2!1).Rec(b_Y218~P!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y218~P)

Fyn ?U ?SH3 SH2 ?PTK Y420 0 ?P Y531 0 ?P Rec fab ?fab b_Y218 P b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 P take all branches, once each, in any order⬇ b_Y224 0 ?P g_Y65_Y76 0 ?P

Fyn phosphorylates Y224 in the beta subunit of the receptor
Fyn bound by its unique domain

Fyn(U!1).Rec(b_Y218~0!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y224~0) -> Fyn(U!1).Rec(b_Y218~0!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y224~P)

Fyn U ?SH3 ?SH2 ?PTK Y420 0 ?P Y531 0 ?P Rec fab ?fab b_Y218 0 b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 P take all branches, once each, in any order⬇ g_Y65_Y76 0 ?P

Fyn bound by its SH2 domain

Fyn(SH2!1).Rec(b_Y218~P!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y224~0) -> Fyn(SH2!1).Rec(b_Y218~P!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,b_Y224~P)

Fyn ?U ?SH3 SH2 ?PTK Y420 0 ?P Y531 0 ?P Rec fab ?fab b_Y218 P b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 P take all branches, once each, in any order⬇ g_Y65_Y76 0 ?P

Fyn phosphorylates Y65 and Y76 in the gamma subunit of the receptor
Fyn bound by its unique domain

Fyn(U!1).Rec(b_Y218~0!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~0) -> Fyn(U!1).Rec(b_Y218~0!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P)

Fyn U ?SH3 ?SH2 ?PTK Y420 0 ?P Y531 0 ?P Rec fab ?fab b_Y218 0 b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 0 P take all branches, once each, in any order⬇

Fyn bound by its SH2 domain

Fyn(SH2!1).Rec(b_Y218~P!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~0) -> Fyn(SH2!1).Rec(b_Y218~P!1,fab!2).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P)

Fyn ?U ?SH3 SH2 ?PTK Y420 0 ?P Y531 0 ?P Rec fab ?fab b_Y218 P b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 0 P take all branches, once each, in any order⬇

# Fyn phosphorylates Syk
Fyn bound by its unique domain

Fyn(U!1).Rec(fab!2,b_Y218~0!1).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P!4).Syk(tSH2!4,Y346~0) -> Fyn(U!1).Rec(fab!2,b_Y218~0!1).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P!4).Syk(tSH2!4,Y346~P)

Fyn U ?SH3 ?SH2 ?PTK Y420 0 ?P Y531 0 ?P Rec fab ?fab b_Y218 0 b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 P Syk tSH2 Y346 0 P take all branches, once each, in any order⬇ ?PTK Y519_Y520 0 ?P

Fyn bound by its SH2 domain

Fyn(SH2!1).Rec(fab!2,b_Y218~P!1).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P!4).Syk(tSH2!4,Y346~0) -> Fyn(SH2!1).Rec(fab!2,b_Y218~P!1).Lig(hap~e!2,hap~e!3).Rec(fab!3,g_Y65_Y76~P!4).Syk(tSH2!4,Y346~P)

Fyn ?U ?SH3 SH2 ?PTK Y420 0 ?P Y531 0 ?P Rec fab ?fab b_Y218 P b_Y224 0 ?P g_Y65_Y76 0 ?P Lig hap e hap e Rec fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 P Syk tSH2 Y346 0 P take all branches, once each, in any order⬇ ?PTK Y519_Y520 0 ?P

# SH3 domain of Fyn binds PRS1 in Pag1
Association when Fyn is free

Fyn(U,SH3,SH2) + Pag1(PRS1,Y165_Y183) -> Fyn(U,SH3!1,SH2).Pag1(PRS1!1,Y165_Y183)

Fyn U ⬇SH3 SH2 ?PTK Y420 0 ?P Y531 0 ?P ⬇ Pag1 ⬇PRS1 Y165_Y183 ?PRS2 Y317 0 ?P Y386_Y409 0 ?P

Association when Fyn is tethered to Pag1 via an SH2 domain-pY interaction

Fyn(U,SH3,SH2!2).Pag1(PRS1,Y165_Y183~P!2) -> Fyn(U,SH3!1,SH2!2).Pag1(PRS1!1,Y165_Y183~P!2)

Fyn U ⬇SH3 SH2 ?PTK Y420 0 ?P Y531 0 ?P Pag1 ⬇PRS1 Y165_Y183 P ?PRS2 Y317 0 ?P Y386_Y409 0 ?P

Dissociation of Fyn SH3

Fyn(SH3!1,SH2).Pag1(PRS1!1,Y165_Y183) -> Fyn(SH3,SH2) + Pag1(PRS1,Y165_Y183)

Fyn ?U ⬆SH3 SH2 ?PTK Y420 0 ?P Y531 0 ?P ⬆ Pag1 ⬆PRS1 Y165_Y183 ?PRS2 Y317 0 ?P Y386_Y409 0 ?P

# SH2 domain of Fyn binds a pY in Pag1
Association when Fyn is free

Fyn(U,SH3,SH2) + Pag1(PRS1,Y165_Y183~P) -> Fyn(U,SH3,SH2!2).Pag1(PRS1,Y165_Y183~P!2)

Fyn U SH3 ⬇SH2 ?PTK Y420 0 ?P Y531 0 ?P ⬇ Pag1 PRS1 Y165_Y183 ⬇P ?PRS2 Y317 0 ?P Y386_Y409 0 ?P

Association when Fyn is tethered to Pag1 via SH3 domain-PRS interaction

Fyn(U,SH3!1,SH2).Pag1(PRS1!1,Y165_Y183~P) -> Fyn(U,SH3!1,SH2!2).Pag1(PRS1!1,Y165_Y183~P!2)

Fyn U SH3 ⬇SH2 ?PTK Y420 0 ?P Y531 0 ?P Pag1 PRS1 Y165_Y183 ⬇P ?PRS2 Y317 0 ?P Y386_Y409 0 ?P

Dissociation of Fyn from Pag1, breaking two-point attachment

Fyn(SH3!1,SH2!2).Pag1(PRS1!1,Y165_Y183~P!2) -> Fyn(SH3,SH2) + Pag1(PRS1,Y165_Y183~P)

Fyn ?U ⬆SH3 ⬆SH2 ?PTK Y420 0 ?P Y531 0 ?P ⬆ Pag1 ⬆PRS1 Y165_Y183 ⬆P ?PRS2 Y317 0 ?P Y386_Y409 0 ?P

Fyn phosphorylates Y386 and Y409 in Pag1

Fyn(SH3,SH2!1,Y531).Pag1(Y386_Y409~0,Y165_Y183~P!1) -> Fyn(SH3,SH2!1,Y531).Pag1(Y386_Y409~P,Y165_Y183~P!1)

Fyn ?U SH3 SH2 ?PTK Y420 0 ?P Y531 Pag1 ?PRS1 Y165_Y183 P ?PRS2 Y317 0 ?P Y386_Y409 0 P take all branches, once each, in any order⬇

Fyn(SH3!2,SH2!1,Y531).Pag1(PRS1!2,Y386_Y409~0,Y165_Y183~P!1) -> Fyn(SH3!2,SH2!1,Y531).Pag1(PRS1!2,Y386_Y409~P,Y165_Y183~P!1)

Fyn ?U SH3 SH2 ?PTK Y420 0 ?P Y531 Pag1 PRS1 Y165_Y183 P ?PRS2 Y317 0 ?P Y386_Y409 0 P take all branches, once each, in any order⬇

Fyn(SH3!1,SH2,Y531).Pag1(PRS1!1,Y386_Y409~0) -> Fyn(SH3!1,SH2,Y531).Pag1(PRS1!1,Y386_Y409~P)

Fyn ?U SH3 SH2 ?PTK Y420 0 ?P Y531 Pag1 PRS1 Y165_Y183 0 ?P ?PRS2 Y317 0 ?P Y386_Y409 0 P take all branches, once each, in any order⬇

Fyn phosphorylates Y317 in Pag1

Fyn(SH3,SH2!1,Y531).Pag1(Y317~0,Y165_Y183~P!1) -> Fyn(SH3,SH2!1,Y531).Pag1(Y317~P,Y165_Y183~P!1)

Fyn ?U SH3 SH2 ?PTK Y420 0 ?P Y531 Pag1 ?PRS1 Y165_Y183 P ?PRS2 Y317 0 P take all branches, once each, in any order⬇ Y386_Y409 0 ?P

Fyn(SH3!2,SH2!1,Y531).Pag1(PRS1!2,Y317~0,Y165_Y183~P!1) -> Fyn(SH3!2,SH2!1,Y531).Pag1(PRS1!2,Y317~P,Y165_Y183~P!1)

Fyn ?U SH3 SH2 ?PTK Y420 0 ?P Y531 Pag1 PRS1 Y165_Y183 P ?PRS2 Y317 0 P take all branches, once each, in any order⬇ Y386_Y409 0 ?P

Fyn(SH3!1,SH2,Y531).Pag1(PRS1!1,Y317~0) -> Fyn(SH3!1,SH2,Y531).Pag1(PRS1!1,Y317~P)

Fyn ?U SH3 SH2 ?PTK Y420 0 ?P Y531 Pag1 PRS1 Y165_Y183 0 ?P ?PRS2 Y317 0 P take all branches, once each, in any order⬇ Y386_Y409 0 ?P

Csk cis phosphorylates Y531 in Fyn

Fyn(SH3,SH2!1,Y531~0).Pag1(Y165_Y183~P!1,Y317~P!2).Csk(SH2!2) -> Fyn(SH3,SH2!1,Y531~P).Pag1(Y165_Y183~P!1,Y317~P!2).Csk(SH2!2)

Fyn ?U SH3 SH2 ?PTK Y420 0 ?P Y531 0 P take all branches, once each, in any order⬇ Pag1 ?PRS1 Y165_Y183 P ?PRS2 Y317 P Y386_Y409 0 ?P Csk SH2

Fyn(SH3!1,SH2,Y531~0).Pag1(PRS1!1,Y317~P!2).Csk(SH2!2) -> Fyn(SH3!1,SH2,Y531~P).Pag1(PRS1!1,Y317~P!2).Csk(SH2!2)

Fyn ?U SH3 SH2 ?PTK Y420 0 ?P Y531 0 P take all branches, once each, in any order⬇ Pag1 PRS1 Y165_Y183 0 ?P ?PRS2 Y317 P Y386_Y409 0 ?P Csk SH2

Fyn(SH3!1,SH2!3,Y531~0).Pag1(PRS1!1,Y165_Y183~P!3,Y317~P!2).Csk(SH2!2) -> Fyn(SH3!1,SH2!3,Y531~P).Pag1(PRS1!1,Y165_Y183~P!3,Y317~P!2).Csk(SH2!2)

Fyn ?U SH3 SH2 ?PTK Y420 0 ?P Y531 0 P take all branches, once each, in any order⬇ Pag1 PRS1 Y165_Y183 P ?PRS2 Y317 P Y386_Y409 0 ?P Csk SH2

Syk phosphorylates Lat Y136

Syk(tSH2!+,PTK) + Lat(Y136~0) -> Syk(tSH2!+,PTK!1).Lat(Y136~0!1)

Syk tSH2 Y346 0 ?P ⬇PTK Y519_Y520 0 ?P ⬇ Lat Y136 ⬇0 Y175 0 ?P

Syk(PTK!1).Lat(Y136~0!1) -> Syk(PTK) + Lat(Y136~0)

Syk ?tSH2 Y346 0 ?P ⬆PTK Y519_Y520 0 ?P ⬆ Lat Y136 ⬆0 Y175 0 ?P

Syk(PTK!1,Y519_Y520~P).Lat(Y136~0!1) -> Syk(PTK,Y519_Y520~P) + Lat(Y136~P)

Syk ?tSH2 Y346 0 ?P ⬆PTK Y519_Y520 P ⬆ Lat Y136 ⬆0 P take all branches, once each, in any order⬇ Y175 0 ?P

Syk(PTK!1,Y519_Y520~0).Lat(Y136~0!1) -> Syk(PTK,Y519_Y520~0) + Lat(Y136~P)

Syk ?tSH2 Y346 0 ?P ⬆PTK Y519_Y520 0 ⬆ Lat Y136 ⬆0 P take all branches, once each, in any order⬇ Y175 0 ?P

Lat pY136 binds Plcg1

Lat(Y136~P) + Plcg1(SH2) <-> Lat(Y136~P!1).Plcg1(SH2!1)

Lat Y136 ⬇⬆P Y175 0 ?P ⬇⬆ Plcg1 ⬇⬆SH2 ?SH3 ?PLC Y783 0 ?P

Syk phosphorylates Lat Y175

Syk(tSH2!+,PTK) + Lat(Y175~0) -> Syk(tSH2!+,PTK!1).Lat(Y175~0!1)

Syk tSH2 Y346 0 ?P ⬇PTK Y519_Y520 0 ?P ⬇ Lat Y136 0 ?P Y175 ⬇0

Syk(PTK!1).Lat(Y175~0!1) -> Syk(PTK) + Lat(Y175~0)

Syk ?tSH2 Y346 0 ?P ⬆PTK Y519_Y520 0 ?P ⬆ Lat Y136 0 ?P Y175 ⬆0

Syk(PTK!1,Y519_Y520~P).Lat(Y175~0!1) -> Syk(PTK,Y519_Y520~P) + Lat(Y175~P)

Syk ?tSH2 Y346 0 ?P ⬆PTK Y519_Y520 P ⬆ Lat Y136 0 ?P Y175 ⬆0 P take all branches, once each, in any order⬇

Syk(PTK!1,Y519_Y520~0).Lat(Y175~0!1) -> Syk(PTK,Y519_Y520~0) + Lat(Y175~P)

Syk ?tSH2 Y346 0 ?P ⬆PTK Y519_Y520 0 ⬆ Lat Y136 0 ?P Y175 ⬆0 P take all branches, once each, in any order⬇

Lat pY175 binds Grb2

Lat(Y175~P) + Grb2(SH2) <-> Lat(Y175~P!1).Grb2(SH2!1)

Lat Y136 0 ?P Y175 ⬇⬆P ⬇⬆ Grb2 ⬇⬆SH2 ?cSH3

Lat pY175 binds Grap2

Lat(Y175~P) + Grap2(SH2) <-> Lat(Y175~P!1).Grap2(SH2!1)

Lat Y136 0 ?P Y175 ⬇⬆P ⬇⬆ Grap2 ⬇⬆SH2 ?SH3

Grap2 binds Lcp2

Grap2(SH3) + Lcp2(RxxK) <-> Grap2(SH3!1).Lcp2(RxxK!1)

Grap2 ?SH2 ⬇⬆SH3 ⬇⬆ Lcp2 ⬇⬆RxxK ?PRS

Grb2 binds Gab2

Grb2(cSH3) + Gab2(PRS) <-> Grb2(cSH3!1).Gab2(PRS!1)

Grb2 ?SH2 ⬇⬆cSH3 ⬇⬆ Gab2 ⬇⬆PRS Y441 0 ?P

Lcp2 binds Plcg1

Lcp2(PRS) + Plcg1(SH3) <-> Lcp2(PRS!1).Plcg1(SH3!1)

Lcp2 ?RxxK ⬇⬆PRS ⬇⬆ Plcg1 ?SH2 ⬇⬆SH3 ?PLC Y783 0 ?P

Fyn phosphorylates Gab2

Fyn(U!+,SH2,PTK) + Lat(Y175~P!1).Grb2(SH2!1,cSH3!2).Gab2(PRS!2,Y441~0) -> Fyn(U!+,SH2,PTK!3).Lat(Y175~P!1).Grb2(SH2!1,cSH3!2).Gab2(PRS!2,Y441~0!3)

Fyn U ?SH3 SH2 ⬇PTK Y420 0 ?P Y531 0 ?P ⬇ Lat Y136 0 ?P Y175 P Grb2 SH2 cSH3 Gab2 PRS Y441 ⬇0

Rec(b_Y218~P!4).Fyn(U,SH2!4,PTK) + Lat(Y175~P!1).Grb2(SH2!1,cSH3!2).Gab2(PRS!2,Y441~0) -> Rec(b_Y218~P!4).Fyn(U,SH2!4,PTK!3).Lat(Y175~P!1).Grb2(SH2!1,cSH3!2).Gab2(PRS!2,Y441~0!3)

Rec ?fab ?fab b_Y218 P b_Y224 0 ?P g_Y65_Y76 0 ?P Fyn U ?SH3 SH2 ⬇PTK Y420 0 ?P Y531 0 ?P ⬇ Lat Y136 0 ?P Y175 P Grb2 SH2 cSH3 Gab2 PRS Y441 ⬇0

Fyn(PTK!1).Gab2(Y441~0!1) -> Fyn(PTK) + Gab2(Y441~0)

Fyn ?U ?SH3 ?SH2 ⬆PTK Y420 0 ?P Y531 0 ?P ⬆ Gab2 ?PRS Y441 ⬆0

Fyn(PTK!1).Gab2(Y441~0!1) -> Fyn(PTK) + Gab2(Y441~P)

Fyn ?U ?SH3 ?SH2 ⬆PTK Y420 0 ?P Y531 0 ?P ⬆ Gab2 ?PRS Y441 ⬆0 P take all branches, once each, in any order⬇

Gab2 binds PI 3-kinase

Gab2(Y441~P) + Pi3k(p85_SH2) <-> Gab2(Y441~P!1).Pi3k(p85_SH2!1)

Gab2 ?PRS Y441 ⬇⬆P ⬇⬆ Pi3k ⬇⬆p85_SH2 ?PI3Kc

PI 3-kinase generates PIP3

Lat(Y175~P!1).Grb2(SH2!1,cSH3!2).Gab2(PRS!2,Y441~P!3).Pi3k(p85_SH2!3,PI3Kc) + PI45P2(bind) -> Lat(Y175~P!1).Grb2(SH2!1,cSH3!2).Gab2(PRS!2,Y441~P!3).Pi3k(p85_SH2!3,PI3Kc!4).PI45P2(bind!4)

Lat Y136 0 ?P Y175 P Grb2 SH2 cSH3 Gab2 PRS Y441 P Pi3k p85_SH2 ⬇PI3Kc ⬇ PI45P2 ⬇bind

Pi3k(PI3Kc!1).PI45P2(bind!1) -> Pi3k(PI3Kc) + PI45P2(bind)

Pi3k ?p85_SH2 ⬆PI3Kc ⬆ PI45P2 ⬆bind

Pi3k(PI3Kc!1).PI45P2(bind!1) -> Pi3k(PI3Kc) + PI345P3(bind) + PI45P2(bind)

Pi3k ?p85_SH2 ⬆PI3Kc ⬆ PI345P3 bind synthesized PI45P2 ⬆bind

Pi3k(PI3Kc!1).PI45P2(bind!1) -> Pi3k(PI3Kc) + PI345P3(bind)

Pi3k ?p85_SH2 ⬆PI3Kc ⬆ PI45P2 ⬆bind degraded PI345P3 bind synthesized

Btk binds PIP3

Btk(PH) + PI345P3(bind) <-> Btk(PH!1).PI345P3(bind!1)

Btk ⬇⬆PH ?PTK ⬇⬆ PI345P3 ⬇⬆bind

Btk phosphorylates Plcg1

Btk(PH!+,PTK) + Plcg1(SH2!+,Y783~0) -> Btk(PH!+,PTK!1).Plcg1(SH2!+,Y783~0!1)

Btk PH ⬇PTK ⬇ Plcg1 SH2 ?SH3 ?PLC Y783 ⬇0

Btk(PTK!1).Plcg1(Y783~0!1) -> Btk(PTK) + Plcg1(Y783~0)

Btk ?PH ⬆PTK ⬆ Plcg1 ?SH2 ?SH3 ?PLC Y783 ⬆0

Btk(PTK!1).Plcg1(Y783~0!1) -> Btk(PTK) + Plcg1(Y783~P)

Btk ?PH ⬆PTK ⬆ Plcg1 ?SH2 ?SH3 ?PLC Y783 ⬆0 P take all branches, once each, in any order⬇

Inpp5d binds phosphorylated Y224 in the beta subunit of the receptor

Inpp5d(SH2,C2) + Rec(b_Y224~P) -> Inpp5d(SH2!1,C2).Rec(b_Y224~P!1)

Inpp5d ⬇SH2 ?IPP C2 ⬇ Rec ?fab ?fab b_Y218 0 ?P b_Y224 ⬇P g_Y65_Y76 0 ?P

Inpp5d(IPP,C2!+) + Rec(b_Y224~P) -> Inpp5d(IPP!1,C2!+).Rec(b_Y224~P!1)

Inpp5d ?SH2 ⬇IPP C2 ⬇ Rec ?fab ?fab b_Y218 0 ?P b_Y224 ⬇P g_Y65_Y76 0 ?P

Inpp5d(SH2!1).Rec(b_Y224~P!1) -> Inpp5d(SH2) + Rec(b_Y224~P)

Inpp5d ⬆SH2 ?IPP ?C2 ⬆ Rec ?fab ?fab b_Y218 0 ?P b_Y224 ⬆P g_Y65_Y76 0 ?P

Inpp5d(SH2!+,IPP) + PI345P3(bind) <-> Inpp5d(SH2!+,IPP!1).PI345P3(bind!1)

Inpp5d SH2 ⬇⬆IPP ?C2 ⬇⬆ PI345P3 ⬇⬆bind

Inpp5d(SH2!+,IPP!1).PI345P3(bind!1) -> Inpp5d(SH2!+,IPP)

Inpp5d SH2 ⬆IPP ?C2 ⬆ PI345P3 ⬆bind degraded

PI345P3(bind) + Sink() -> Sink()

PI345P3 bind degraded Sink

Other lipid reactions

PI345P3(bind) -> PI45P2(bind)

PI345P3 bind degraded PI45P2 bind synthesized

PI4P() -> PI45P2(bind)

PI4P degraded PI45P2 bind synthesized

PI45P2(bind) -> PI4P()

PI45P2 bind degraded PI4P synthesized

Nonspecific phosphorylation and dephosphorylation

Rec(b_Y218~0) -> Rec(b_Y218~P)

Rec ?fab ?fab b_Y218 0 P take all branches, once each, in any order⬇ b_Y224 0 ?P g_Y65_Y76 0 ?P

Rec(b_Y218~P) -> Rec(b_Y218~0)

Rec ?fab ?fab b_Y218 0 P take one or more branches, once each, in any order⬆ b_Y224 0 ?P g_Y65_Y76 0 ?P

Rec(b_Y224~0) -> Rec(b_Y224~P)

Rec ?fab ?fab b_Y218 0 ?P b_Y224 0 P take all branches, once each, in any order⬇ g_Y65_Y76 0 ?P

Rec(b_Y224~P) -> Rec(b_Y224~0)

Rec ?fab ?fab b_Y218 0 ?P b_Y224 0 P take one or more branches, once each, in any order⬆ g_Y65_Y76 0 ?P

Rec(g_Y65_Y76~0) -> Rec(g_Y65_Y76~P)

Rec ?fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 0 P take all branches, once each, in any order⬇

Rec(g_Y65_Y76~P) -> Rec(g_Y65_Y76~0)

Rec ?fab ?fab b_Y218 0 ?P b_Y224 0 ?P g_Y65_Y76 0 P take one or more branches, once each, in any order⬆

Lyn(Y508~0) -> Lyn(Y508~P)

Lyn ?U ?SH3 ?SH2 Y397 0 ?P Y508 0 P take all branches, once each, in any order⬇

Lyn(Y508~P) -> Lyn(Y508~0)

Lyn ?U ?SH3 ?SH2 Y397 0 ?P Y508 0 P take one or more branches, once each, in any order⬆

Fyn(Y531~0) -> Fyn(Y531~P)

Fyn ?U ?SH3 ?SH2 ?PTK Y420 0 ?P Y531 0 P take all branches, once each, in any order⬇

Fyn(Y531~P) -> Fyn(Y531~0)

Fyn ?U ?SH3 ?SH2 ?PTK Y420 0 ?P Y531 0 P take one or more branches, once each, in any order⬆

Syk(Y346~0) -> Syk(Y346~P)

Syk ?tSH2 Y346 0 P take all branches, once each, in any order⬇ ?PTK Y519_Y520 0 ?P

Syk(Y346~P) -> Syk(Y346~0)

Syk ?tSH2 Y346 0 P take one or more branches, once each, in any order⬆ ?PTK Y519_Y520 0 ?P

Syk(Y519_Y520~0) -> Syk(Y519_Y520~P)

Syk ?tSH2 Y346 0 ?P ?PTK Y519_Y520 0 P take all branches, once each, in any order⬇

Syk(Y519_Y520~P) -> Syk(Y519_Y520~0)

Syk ?tSH2 Y346 0 ?P ?PTK Y519_Y520 0 P take one or more branches, once each, in any order⬆

Pag1(Y317~0) -> Pag1(Y317~P)

Pag1 ?PRS1 Y165_Y183 0 ?P ?PRS2 Y317 0 P take all branches, once each, in any order⬇ Y386_Y409 0 ?P

Pag1(Y317~P) -> Pag1(Y317~0)

Pag1 ?PRS1 Y165_Y183 0 ?P ?PRS2 Y317 0 P take one or more branches, once each, in any order⬆ Y386_Y409 0 ?P

Pag1(Y165_Y183~0) -> Pag1(Y165_Y183~P)

Pag1 ?PRS1 Y165_Y183 0 P take all branches, once each, in any order⬇ ?PRS2 Y317 0 ?P Y386_Y409 0 ?P

Pag1(Y165_Y183~P) -> Pag1(Y165_Y183~0)

Pag1 ?PRS1 Y165_Y183 0 P take one or more branches, once each, in any order⬆ ?PRS2 Y317 0 ?P Y386_Y409 0 ?P

Pag1(Y386_Y409~0) -> Pag1(Y386_Y409~P)

Pag1 ?PRS1 Y165_Y183 0 ?P ?PRS2 Y317 0 ?P Y386_Y409 0 P take all branches, once each, in any order⬇

Pag1(Y386_Y409~P) -> Pag1(Y386_Y409~0)

Pag1 ?PRS1 Y165_Y183 0 ?P ?PRS2 Y317 0 ?P Y386_Y409 0 P take one or more branches, once each, in any order⬆

Gab2(Y441~0) -> Gab2(Y441~P)

Gab2 ?PRS Y441 0 P take all branches, once each, in any order⬇

Gab2(Y441~P) -> Gab2(Y441~0)

Gab2 ?PRS Y441 0 P take one or more branches, once each, in any order⬆

Lat(Y136~0) -> Lat(Y136~P)

Lat Y136 0 P take all branches, once each, in any order⬇ Y175 0 ?P

Lat(Y136~P) -> Lat(Y136~0)

Lat Y136 0 P take one or more branches, once each, in any order⬆ Y175 0 ?P

Lat(Y175~0) -> Lat(Y175~P)

Lat Y136 0 ?P Y175 0 P take all branches, once each, in any order⬇

Lat(Y175~P) -> Lat(Y175~0)

Lat Y136 0 ?P Y175 0 P take one or more branches, once each, in any order⬆

Plcg1(Y783~0) -> Plcg1(Y783~P)

Plcg1 ?SH2 ?SH3 ?PLC Y783 0 P take all branches, once each, in any order⬇

Plcg1(Y783~P) -> Plcg1(Y783~0)

Plcg1 ?SH2 ?SH3 ?PLC Y783 0 P take one or more branches, once each, in any order⬆