Molecules

The molecule types are illustrated by nested boxes in Fig. 1B cell antigen receptorY188 and Y199 in the Ig-alpha ITAM are lumped togetherY196 and Y207 in the Ig-beta ITAM are lumped together0, unphosphorylated; P, singly phosphorylated; PP, doubly phosphorylated

BCR(Y188_Y199~0~P~PP,Y196_Y207~0~P~PP)

BCR Y188_Y199 0 P PP Y196_Y207 0 P PP
Src-family kinase LynY397, A-loop tyrosineY508, C-terminal regulatory tyrosine0, unphosphorylated; P, phosphorylated

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

Lyn unique SH3 SH2 Y397 0 P Y508 0 P
Src-family kinase Fyn (FynT isoform)Y420, A-loop tyrosineY531, C-terminal regulatory tyrosine0, unphosphorylated; P, phosphorylated

Fyn(unique,SH3,SH2,Y420~0~P,Y531~0~P)

Fyn unique SH3 SH2 Y420 0 P Y531 0 P
Protein tyrosine kinase Csk

Csk(SH2)

Csk SH2
Adapter protein PAG (aka Cbp)PRS1, proline-rich sequence recognized by SH3 domain of FynPRS2, proline-rich sequence recognized by SH3 domain of LynY163 and Y181 are lumped together (docking sites for SH2 domain of Fyn)Y387 and Y417 are lumped together (docking sites for SH2 domain of Lyn)Y317, docking site of Csk0, unphosphorylated; P, phosphorylated

PAG(PRS1,PRS2,Y317~0~P,Y163_Y181~0~P,Y387_Y417~0~P)

PAG PRS1 PRS2 Y317 0 P Y163_Y181 0 P Y387_Y417 0 P
Protein tyrosine kinase SyktSH2, the tandem SH2 domains of Syk are lumped togetherY525 and Y526 in the activation loop of Syk are lumped together

Syk(tSH2,Y525_Y526~0~P)

Syk tSH2 Y525_Y526 0 P

Species

BCR(Y188_Y199~0,Y196_Y207~0)

BCR Y188_Y199 0 Y196_Y207 0

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

Lyn unique SH3 SH2 Y397 0 Y508 0

Fyn(unique,SH3,SH2,Y420~0,Y531~0)

Fyn unique SH3 SH2 Y420 0 Y531 0

PAG(PRS1,PRS2,Y317~0,Y163_Y181~0,Y387_Y417~0)

PAG PRS1 PRS2 Y317 0 Y163_Y181 0 Y387_Y417 0

Csk(SH2)

Csk SH2

Syk(tSH2,Y525_Y526~0)

Syk tSH2 Y525_Y526 0

Observables

Syk(Y525_Y526~P)

Syk tSH2 Y525_Y526 P

BCR(Y188_Y199~P)

BCR Y188_Y199 P Y196_Y207 0 P PP

BCR(Y188_Y199~PP)

BCR Y188_Y199 PP Y196_Y207 0 P PP

BCR(Y196_Y207~PP)

BCR Y188_Y199 0 P PP Y196_Y207 PP

Lyn(Y397~P)

Lyn unique SH3 SH2 Y397 P Y508 0 P

Lyn(Y508~P!+)

Lyn unique SH3 SH2 Y397 0 P Y508 P

Fyn(Y420~P)

Fyn unique SH3 SH2 Y420 P Y531 0 P

Fyn(Y531~P!+)

Fyn unique SH3 SH2 Y420 0 P Y531 P

PAG(Y317~P!+)

PAG PRS1 PRS2 Y317 P Y163_Y181 0 P Y387_Y417 0 P

Reaction Rules

The following 25 sets of rules are represented by Arrows 1-25 in Fig. 1The rules within a set share a common reaction centerArrow 1unique domain of Lyn binds unphosphorylated Ig-alpha ITAM

BCR(Y188_Y199~0) + Lyn(unique,SH3,SH2) <-> BCR(Y188_Y199~0!1).Lyn(unique!1,SH3,SH2)

BCR Y188_Y199 1 ⬆⬇0 Y196_Y207 0 P PP Lyn 1 ⬆⬇unique SH3 SH2 Y397 0 P Y508 0 P
Arrow 2SH2 domain of Lyn binds phosphorylated Ig-alpha ITAM

BCR(Y188_Y199~P) + Lyn(unique,SH3,SH2) <-> BCR(Y188_Y199~P!1).Lyn(unique,SH3,SH2!1)

BCR Y188_Y199 1 ⬆⬇P Y196_Y207 0 P PP Lyn unique SH3 1 ⬆⬇SH2 Y397 0 P Y508 0 P

BCR(Y188_Y199~PP) + Lyn(unique,SH3,SH2) <-> BCR(Y188_Y199~PP!1).Lyn(unique,SH3,SH2!1)

BCR Y188_Y199 1 ⬆⬇PP Y196_Y207 0 P PP Lyn unique SH3 1 ⬆⬇SH2 Y397 0 P Y508 0 P
Arrow 3autoinhibition of Lyn, SH2 domain of Lyn binds C-terminal pY

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

Lyn unique SH3 1 ⬆⬇SH2 Y397 0 P Y508 1 ⬆⬇P
Arrow 4Lyn phosphorylates Ig-alpha ITAM

Lyn(Y397~0).BCR() + BCR(Y188_Y199~0) -> Lyn(Y397~0).BCR() + BCR(Y188_Y199~P)

Lyn unique SH3 SH2 Y397 0 Y508 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P take all branches, once each, in any order⬇⬇ Y196_Y207 0 P PP

Lyn(Y397~0).BCR() + BCR(Y188_Y199~P) -> Lyn(Y397~0).BCR() + BCR(Y188_Y199~PP)

Lyn unique SH3 SH2 Y397 0 Y508 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 P PP take all branches, once each, in any order⬇⬇ Y196_Y207 0 P PP

Lyn(Y397~P).BCR() + BCR(Y188_Y199~0) -> Lyn(Y397~P).BCR() + BCR(Y188_Y199~P)

Lyn unique SH3 SH2 Y397 P Y508 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P take all branches, once each, in any order⬇⬇ Y196_Y207 0 P PP

Lyn(Y397~P).BCR() + BCR(Y188_Y199~P) -> Lyn(Y397~P).BCR() + BCR(Y188_Y199~PP)

Lyn unique SH3 SH2 Y397 P Y508 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 P PP take all branches, once each, in any order⬇⬇ Y196_Y207 0 P PP
Arrow 5Lyn phosphorylates Ig-beta ITAM

Lyn(Y397~0).BCR() + BCR(Y196_Y207~0) -> Lyn(Y397~0).BCR() + BCR(Y196_Y207~P)

Lyn unique SH3 SH2 Y397 0 Y508 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 0 P take all branches, once each, in any order⬇⬇

Lyn(Y397~0).BCR() + BCR(Y196_Y207~P) -> Lyn(Y397~0).BCR() + BCR(Y196_Y207~PP)

Lyn unique SH3 SH2 Y397 0 Y508 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 P PP take all branches, once each, in any order⬇⬇

Lyn(Y397~P).BCR() + BCR(Y196_Y207~0) -> Lyn(Y397~P).BCR() + BCR(Y196_Y207~P)

Lyn unique SH3 SH2 Y397 P Y508 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 0 P take all branches, once each, in any order⬇⬇

Lyn(Y397~P).BCR() + BCR(Y196_Y207~P) -> Lyn(Y397~P).BCR() + BCR(Y196_Y207~PP)

Lyn unique SH3 SH2 Y397 P Y508 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 P PP take all branches, once each, in any order⬇⬇
Arrow 6trans autophosphorylation of Lynreceptor-bound Lyn phosphorylates receptor-bound Lyn

Lyn(Y397~0).BCR() + BCR().Lyn(Y397~0) -> Lyn(Y397~0).BCR() + BCR().Lyn(Y397~P)

Lyn unique SH3 SH2 Y397 0 Y508 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 0 P PP Lyn unique SH3 SH2 Y397 0 P take all branches, once each, in any order⬇⬇ Y508 0 P

Lyn(Y397~P).BCR() + BCR().Lyn(Y397~0) -> Lyn(Y397~P).BCR() + BCR().Lyn(Y397~P)

Lyn unique SH3 SH2 Y397 P Y508 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 0 P PP Lyn unique SH3 SH2 Y397 0 P take all branches, once each, in any order⬇⬇ Y508 0 P
free Lyn phosphorylates free Lyn

Lyn(unique,SH3,SH2,Y397~0,Y508~0) + Lyn(unique,SH3,SH2,Y397~0,Y508~0) -> Lyn(unique,SH3,SH2,Y397~0,Y508~0) + Lyn(unique,SH3,SH2,Y397~P,Y508~0)

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

Lyn(unique,SH3,SH2,Y397~P,Y508~0) + Lyn(unique,SH3,SH2,Y397~0,Y508~0) -> Lyn(unique,SH3,SH2,Y397~P,Y508~0) + Lyn(unique,SH3,SH2,Y397~P,Y508~0)

Lyn unique SH3 SH2 Y397 P Y508 0 Lyn unique SH3 SH2 Y397 0 P take all branches, once each, in any order⬇⬇ Y508 0
Arrow 7Lyn phosphorylates Fynreceptor-bound Lyn phosphorylates receptor-bound Fyn

Lyn(Y397~0).BCR() + BCR().Fyn(Y420~0) -> Lyn(Y397~0).BCR() + BCR().Fyn(Y420~P)

Lyn unique SH3 SH2 Y397 0 Y508 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 0 P PP Fyn unique SH3 SH2 Y420 0 P take all branches, once each, in any order⬇⬇ Y531 0 P

Lyn(Y397~P).BCR() + BCR().Fyn(Y420~0) -> Lyn(Y397~P).BCR() + BCR().Fyn(Y420~P)

Lyn unique SH3 SH2 Y397 P Y508 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 0 P PP Fyn unique SH3 SH2 Y420 0 P take all branches, once each, in any order⬇⬇ Y531 0 P
free Lyn phosphorylates free Fyn

Lyn(unique,SH3,SH2,Y397~0,Y508~0) + Fyn(unique,SH3,SH2,Y420~0,Y531~0) -> Lyn(unique,SH3,SH2,Y397~0,Y508~0) + Fyn(unique,SH3,SH2,Y420~P,Y531~0)

Lyn unique SH3 SH2 Y397 0 Y508 0 Fyn unique SH3 SH2 Y420 0 P take all branches, once each, in any order⬇⬇ Y531 0

Lyn(unique,SH3,SH2,Y397~P,Y508~0) + Fyn(unique,SH3,SH2,Y420~0,Y531~0) -> Lyn(unique,SH3,SH2,Y397~P,Y508~0) + Fyn(unique,SH3,SH2,Y420~P,Y531~0)

Lyn unique SH3 SH2 Y397 P Y508 0 Fyn unique SH3 SH2 Y420 0 P take all branches, once each, in any order⬇⬇ Y531 0
Arrow 8Lyn phosphorylates PAG

Lyn(Y397~P,Y508).PAG(Y387_Y417~0) -> Lyn(Y397~P,Y508).PAG(Y387_Y417~P)

Lyn unique SH3 SH2 Y397 P Y508 PAG PRS1 PRS2 Y317 0 P Y163_Y181 0 P Y387_Y417 0 P take all branches, once each, in any order⬇⬇

Lyn(SH2!1,Y397~P,Y508).PAG(Y163_Y181~0,Y387_Y417~P!1) -> Lyn(SH2!1,Y397~P,Y508).PAG(Y163_Y181~P,Y387_Y417~P!1)

Lyn unique SH3 1SH2 Y397 P Y508 PAG PRS1 PRS2 Y317 0 P Y163_Y181 0 P take all branches, once each, in any order⬇⬇ Y387_Y417 1P

Lyn(SH2!1,Y397~P,Y508).PAG(Y317~0,Y387_Y417~P!1) -> Lyn(SH2!1,Y397~P,Y508).PAG(Y317~P,Y387_Y417~P!1)

Lyn unique SH3 1SH2 Y397 P Y508 PAG PRS1 PRS2 Y317 0 P take all branches, once each, in any order⬇⬇ Y163_Y181 0 P Y387_Y417 1P
Arrow 9unique domain of Fyn binds unphosphorylated Ig-alpha ITAM

BCR(Y188_Y199~0) + Fyn(unique,SH3,SH2) <-> BCR(Y188_Y199~0!1).Fyn(unique!1,SH3,SH2)

BCR Y188_Y199 1 ⬆⬇0 Y196_Y207 0 P PP Fyn 1 ⬆⬇unique SH3 SH2 Y420 0 P Y531 0 P
Arrow 10SH2 domain of Fyn binds phosphorylated Ig-alpha ITAM

BCR(Y188_Y199~P) + Fyn(unique,SH3,SH2) <-> BCR(Y188_Y199~P!1).Fyn(unique,SH3,SH2!1)

BCR Y188_Y199 1 ⬆⬇P Y196_Y207 0 P PP Fyn unique SH3 1 ⬆⬇SH2 Y420 0 P Y531 0 P

BCR(Y188_Y199~PP) + Fyn(unique,SH3,SH2) <-> BCR(Y188_Y199~PP!1).Fyn(unique,SH3,SH2!1)

BCR Y188_Y199 1 ⬆⬇PP Y196_Y207 0 P PP Fyn unique SH3 1 ⬆⬇SH2 Y420 0 P Y531 0 P
Arrow 11autoinhibition of Fyn, SH2 domain of Fyn binds C-terminal pY

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

Fyn unique SH3 1 ⬆⬇SH2 Y420 0 P Y531 1 ⬆⬇P
Arrow 12Fyn phosphorylates Ig-beta ITAM

Fyn(Y420~0).BCR() + BCR(Y196_Y207~0) -> Fyn(Y420~0).BCR() + BCR(Y196_Y207~P)

Fyn unique SH3 SH2 Y420 0 Y531 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 0 P take all branches, once each, in any order⬇⬇

Fyn(Y420~0).BCR() + BCR(Y196_Y207~P) -> Fyn(Y420~0).BCR() + BCR(Y196_Y207~PP)

Fyn unique SH3 SH2 Y420 0 Y531 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 P PP take all branches, once each, in any order⬇⬇

Fyn(Y420~P).BCR() + BCR(Y196_Y207~0) -> Fyn(Y420~P).BCR() + BCR(Y196_Y207~P)

Fyn unique SH3 SH2 Y420 P Y531 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 0 P take all branches, once each, in any order⬇⬇

Fyn(Y420~P).BCR() + BCR(Y196_Y207~P) -> Fyn(Y420~P).BCR() + BCR(Y196_Y207~PP)

Fyn unique SH3 SH2 Y420 P Y531 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 P PP take all branches, once each, in any order⬇⬇
Arrow 13Fyn phosphorylates Ig-alpha ITAM

Fyn(Y420~0).BCR() + BCR(Y188_Y199~0) -> Fyn(Y420~0).BCR() + BCR(Y188_Y199~P)

Fyn unique SH3 SH2 Y420 0 Y531 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P take all branches, once each, in any order⬇⬇ Y196_Y207 0 P PP

Fyn(Y420~0).BCR() + BCR(Y188_Y199~P) -> Fyn(Y420~0).BCR() + BCR(Y188_Y199~PP)

Fyn unique SH3 SH2 Y420 0 Y531 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 P PP take all branches, once each, in any order⬇⬇ Y196_Y207 0 P PP

Fyn(Y420~P).BCR() + BCR(Y188_Y199~0) -> Fyn(Y420~P).BCR() + BCR(Y188_Y199~P)

Fyn unique SH3 SH2 Y420 P Y531 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P take all branches, once each, in any order⬇⬇ Y196_Y207 0 P PP

Fyn(Y420~P).BCR() + BCR(Y188_Y199~P) -> Fyn(Y420~P).BCR() + BCR(Y188_Y199~PP)

Fyn unique SH3 SH2 Y420 P Y531 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 P PP take all branches, once each, in any order⬇⬇ Y196_Y207 0 P PP
Arrow 14trans autophosphorylation of Fynreceptor-bound Fyn phosphorylates receptor-bound Fyn

Fyn(Y420~0).BCR() + BCR().Fyn(Y420~0) -> Fyn(Y420~0).BCR() + BCR().Fyn(Y420~P)

Fyn unique SH3 SH2 Y420 0 Y531 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 0 P PP Fyn unique SH3 SH2 Y420 0 P take all branches, once each, in any order⬇⬇ Y531 0 P

Fyn(Y420~P).BCR() + BCR().Fyn(Y420~0) -> Fyn(Y420~P).BCR() + BCR().Fyn(Y420~P)

Fyn unique SH3 SH2 Y420 P Y531 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 0 P PP Fyn unique SH3 SH2 Y420 0 P take all branches, once each, in any order⬇⬇ Y531 0 P
free Fyn phosphorylates free Fyn

Fyn(unique,SH3,SH2,Y420~0,Y531~0) + Fyn(unique,SH3,SH2,Y420~0,Y531~0) -> Fyn(unique,SH3,SH2,Y420~0,Y531~0) + Fyn(unique,SH3,SH2,Y420~P,Y531~0)

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

Fyn(unique,SH3,SH2,Y420~P,Y531~0) + Fyn(unique,SH3,SH2,Y420~0,Y531~0) -> Fyn(unique,SH3,SH2,Y420~P,Y531~0) + Fyn(unique,SH3,SH2,Y420~P,Y531~0)

Fyn unique SH3 SH2 Y420 P Y531 0 Fyn unique SH3 SH2 Y420 0 P take all branches, once each, in any order⬇⬇ Y531 0
Arrow 15Fyn phosphorylates Lynreceptor-bound Fyn phosphorylates receptor-bound Lyn

Fyn(Y420~0).BCR() + BCR().Lyn(Y397~0) -> Fyn(Y420~0).BCR() + BCR().Lyn(Y397~P)

Fyn unique SH3 SH2 Y420 0 Y531 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 0 P PP Lyn unique SH3 SH2 Y397 0 P take all branches, once each, in any order⬇⬇ Y508 0 P

Fyn(Y420~P).BCR() + BCR().Lyn(Y397~0) -> Fyn(Y420~P).BCR() + BCR().Lyn(Y397~P)

Fyn unique SH3 SH2 Y420 P Y531 0 P BCR Y188_Y199 0 P PP Y196_Y207 0 P PP BCR Y188_Y199 0 P PP Y196_Y207 0 P PP Lyn unique SH3 SH2 Y397 0 P take all branches, once each, in any order⬇⬇ Y508 0 P
free Fyn phosphorylates free Lyn

Fyn(unique,SH3,SH2,Y420~0,Y531~0) + Lyn(unique,SH3,SH2,Y397~0,Y508~0) -> Fyn(unique,SH3,SH2,Y420~0,Y531~0) + Lyn(unique,SH3,SH2,Y397~P,Y508~0)

Fyn unique SH3 SH2 Y420 0 Y531 0 Lyn unique SH3 SH2 Y397 0 P take all branches, once each, in any order⬇⬇ Y508 0

Fyn(unique,SH3,SH2,Y420~P,Y531~0) + Lyn(unique,SH3,SH2,Y397~0,Y508~0) -> Fyn(unique,SH3,SH2,Y420~P,Y531~0) + Lyn(unique,SH3,SH2,Y397~P,Y508~0)

Fyn unique SH3 SH2 Y420 P Y531 0 Lyn unique SH3 SH2 Y397 0 P take all branches, once each, in any order⬇⬇ Y508 0
Arrow 16Fyn phosphorylates PAG

Fyn(SH2!1,Y420~P,Y531).PAG(Y163_Y181~P!1,Y387_Y417~0) -> Fyn(SH2!1,Y420~P,Y531).PAG(Y163_Y181~P!1,Y387_Y417~P)

Fyn unique SH3 1SH2 Y420 P Y531 PAG PRS1 PRS2 Y317 0 P Y163_Y181 1P Y387_Y417 0 P take all branches, once each, in any order⬇⬇

Fyn(Y420~P,Y531).PAG(Y163_Y181~0) -> Fyn(Y420~P,Y531).PAG(Y163_Y181~P)

Fyn unique SH3 SH2 Y420 P Y531 PAG PRS1 PRS2 Y317 0 P Y163_Y181 0 P take all branches, once each, in any order⬇⬇ Y387_Y417 0 P

Fyn(SH2!1,Y420~P,Y531).PAG(Y163_Y181~P!1,Y317~0) -> Fyn(SH2!1,Y420~P,Y531).PAG(Y163_Y181~P!1,Y317~P)

Fyn unique SH3 1SH2 Y420 P Y531 PAG PRS1 PRS2 Y317 0 P take all branches, once each, in any order⬇⬇ Y163_Y181 1P Y387_Y417 0 P
Arrow 17tandem SH2 domains of Syk bind doubly phosphorylated Ig-beta ITAM

Syk(tSH2) + BCR(Y196_Y207~PP) <-> Syk(tSH2!1).BCR(Y196_Y207~PP!1)

Syk 1 ⬆⬇tSH2 Y525_Y526 0 P BCR Y188_Y199 0 P PP Y196_Y207 1 ⬆⬇PP
Arrow 18trans autophosphorylation of receptor-bound Syk

Syk(tSH2!+,Y525_Y526~0) + Syk(tSH2!+,Y525_Y526~0) -> Syk(tSH2!+,Y525_Y526~0) + Syk(tSH2!+,Y525_Y526~P)

Syk tSH2 Y525_Y526 0 Syk tSH2 Y525_Y526 0 P take all branches, once each, in any order⬇⬇

Syk(tSH2!+,Y525_Y526~P) + Syk(tSH2!+,Y525_Y526~0) -> Syk(tSH2!+,Y525_Y526~P) + Syk(tSH2!+,Y525_Y526~P)

Syk tSH2 Y525_Y526 P Syk tSH2 Y525_Y526 0 P take all branches, once each, in any order⬇⬇
Arrow 19SH3 domain of Lyn binds PRS2 in PAGassociation, Lyn is free

Lyn(unique,SH3,SH2) + PAG(PRS2,Y387_Y417) -> Lyn(unique,SH3!1,SH2).PAG(PRS2!1,Y387_Y417)

Lyn unique 1 ⬇SH3 SH2 Y397 0 P Y508 0 P PAG PRS1 1 ⬇PRS2 Y317 0 P Y163_Y181 0 P Y387_Y417
dissociation

Lyn(unique,SH3!1,SH2).PAG(PRS2!1,Y387_Y417) -> Lyn(unique,SH3,SH2) + PAG(PRS2,Y387_Y417)

Lyn unique 1 ⬆SH3 SH2 Y397 0 P Y508 0 P PAG PRS1 1 ⬆PRS2 Y317 0 P Y163_Y181 0 P Y387_Y417
association, Lyn is tethered to PAG (via SH2 domain-pY interaction)Lyn, already tethered in PAG by SH2, binds PAG via SH3 domain

Lyn(unique,SH3,SH2!2).PAG(PRS2,Y387_Y417~P!2) -> Lyn(unique,SH3!1,SH2!2).PAG(PRS2!1,Y387_Y417~P!2)

Lyn unique 1 ⬇SH3 2SH2 Y397 0 P Y508 0 P PAG PRS1 1 ⬇PRS2 Y317 0 P Y163_Y181 0 P Y387_Y417 2P
Arrow 20SH2 domain of Lyn binds a pY docking site in PAGassociation, Lyn is free

Lyn(unique,SH3,SH2) + PAG(PRS2,Y387_Y417~P) -> Lyn(unique,SH3,SH2!2).PAG(PRS2,Y387_Y417~P!2)

Lyn unique SH3 2 ⬇SH2 Y397 0 P Y508 0 P PAG PRS1 PRS2 Y317 0 P Y163_Y181 0 P Y387_Y417 2 ⬇P
association, Lyn is tethered to PAG (via SH3 domain-PRS interaction)

Lyn(unique,SH3!1,SH2).PAG(PRS2!1,Y387_Y417~P) -> Lyn(unique,SH3!1,SH2!2).PAG(PRS2!1,Y387_Y417~P!2)

Lyn unique 1SH3 2 ⬇SH2 Y397 0 P Y508 0 P PAG PRS1 1PRS2 Y317 0 P Y163_Y181 0 P Y387_Y417 2 ⬇P
release, breaking two-point attachment

Lyn(unique,SH3!1,SH2!2).PAG(PRS2!1,Y387_Y417~P!2) -> Lyn(unique,SH3,SH2) + PAG(PRS2,Y387_Y417~P)

Lyn unique 1 ⬆SH3 2 ⬆SH2 Y397 0 P Y508 0 P PAG PRS1 1 ⬆PRS2 Y317 0 P Y163_Y181 0 P Y387_Y417 2 ⬆P
Arrow 21SH3 domain of Fyn binds PRS1 in PAGassociation, Fyn is free

Fyn(unique,SH3,SH2) + PAG(PRS1,Y163_Y181) -> Fyn(unique,SH3!1,SH2).PAG(PRS1!1,Y163_Y181)

Fyn unique 1 ⬇SH3 SH2 Y420 0 P Y531 0 P PAG 1 ⬇PRS1 PRS2 Y317 0 P Y163_Y181 Y387_Y417 0 P
dissociation

Fyn(unique,SH3!1,SH2).PAG(PRS1!1,Y163_Y181) -> Fyn(unique,SH3,SH2) + PAG(PRS1,Y163_Y181)

Fyn unique 1 ⬆SH3 SH2 Y420 0 P Y531 0 P PAG 1 ⬆PRS1 PRS2 Y317 0 P Y163_Y181 Y387_Y417 0 P
association, Fyn is tethered to PAG (via SH2 domain-pY interaction)

Fyn(unique,SH3,SH2!2).PAG(PRS1,Y163_Y181~P!2) -> Fyn(unique,SH3!1,SH2!2).PAG(PRS1!1,Y163_Y181~P!2)

Fyn unique 1 ⬇SH3 2SH2 Y420 0 P Y531 0 P PAG 1 ⬇PRS1 PRS2 Y317 0 P Y163_Y181 2P Y387_Y417 0 P
Arrow 22SH2 domain of Fyn binds a pY docking site in PAGassociation, Fyn is free

Fyn(unique,SH3,SH2) + PAG(PRS1,Y163_Y181~P) -> Fyn(unique,SH3,SH2!2).PAG(PRS1,Y163_Y181~P!2)

Fyn unique SH3 2 ⬇SH2 Y420 0 P Y531 0 P PAG PRS1 PRS2 Y317 0 P Y163_Y181 2 ⬇P Y387_Y417 0 P
association, Fyn is tethered to PAG (via SH3 domain-PRS interaction)

Fyn(unique,SH3!1,SH2).PAG(PRS1!1,Y163_Y181~P) -> Fyn(unique,SH3!1,SH2!2).PAG(PRS1!1,Y163_Y181~P!2)

Fyn unique 1SH3 2 ⬇SH2 Y420 0 P Y531 0 P PAG 1PRS1 PRS2 Y317 0 P Y163_Y181 2 ⬇P Y387_Y417 0 P
release, breaking two-point attachment

Fyn(unique,SH3!1,SH2!2).PAG(PRS1!1,Y163_Y181~P!2) -> Fyn(unique,SH3,SH2) + PAG(PRS1,Y163_Y181~P)

Fyn unique 1 ⬆SH3 2 ⬆SH2 Y420 0 P Y531 0 P PAG 1 ⬆PRS1 PRS2 Y317 0 P Y163_Y181 2 ⬆P Y387_Y417 0 P
Arrow 23SH2 domain of Csk binds pY317 docking site in PAG

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

Csk 3 ⬆⬇SH2 PAG PRS1 PRS2 Y317 3 ⬆⬇P Y163_Y181 0 P Y387_Y417 0 P
Arrow 24Csk cis phosphorylates C-terminal Y in Lyn

Lyn(Y508~0).PAG().Csk() -> Lyn(Y508~P).PAG().Csk()

Lyn unique SH3 SH2 Y397 0 P Y508 0 P take all branches, once each, in any order⬇⬇ PAG PRS1 PRS2 Y317 0 P Y163_Y181 0 P Y387_Y417 0 P Csk SH2
Arrow 25Csk cis phosphorylates C-terminal Y in Fyn

Fyn(Y531~0).PAG().Csk() -> Fyn(Y531~P).PAG().Csk()

Fyn unique SH3 SH2 Y420 0 P Y531 0 P take all branches, once each, in any order⬇⬇ PAG PRS1 PRS2 Y317 0 P Y163_Y181 0 P Y387_Y417 0 P Csk SH2
The following rules are NOT illustrated in Fig. 1Dephosphorylation of Ig-alpha

BCR(Y188_Y199~P) -> BCR(Y188_Y199~0)

BCR Y188_Y199 0 P take one or more branches, once each, in any order⬆⬆ Y196_Y207 0 P PP

BCR(Y188_Y199~PP) -> BCR(Y188_Y199~P)

BCR Y188_Y199 P PP take one or more branches, once each, in any order⬆⬆ Y196_Y207 0 P PP
Dephosphorylation of Ig-beta

BCR(Y196_Y207~P) -> BCR(Y196_Y207~0)

BCR Y188_Y199 0 P PP Y196_Y207 0 P take one or more branches, once each, in any order⬆⬆

BCR(Y196_Y207~PP) -> BCR(Y196_Y207~P)

BCR Y188_Y199 0 P PP Y196_Y207 P PP take one or more branches, once each, in any order⬆⬆
Dephosphorylation of Lyn

Lyn(Y397~P) -> Lyn(Y397~0)

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

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

Lyn unique SH3 SH2 Y397 0 P Y508 0 P take one or more branches, once each, in any order⬆⬆
Dephosphorylation of Fyn

Fyn(Y420~P) -> Fyn(Y420~0)

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

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

Fyn unique SH3 SH2 Y420 0 P Y531 0 P take one or more branches, once each, in any order⬆⬆
Dephosphorylation of PAG

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

PAG PRS1 PRS2 Y317 0 P take one or more branches, once each, in any order⬆⬆ Y163_Y181 0 P Y387_Y417 0 P

PAG(Y387_Y417~P) -> PAG(Y387_Y417~0)

PAG PRS1 PRS2 Y317 0 P Y163_Y181 0 P Y387_Y417 0 P take one or more branches, once each, in any order⬆⬆

PAG(Y163_Y181~P) -> PAG(Y163_Y181~0)

PAG PRS1 PRS2 Y317 0 P Y163_Y181 0 P take one or more branches, once each, in any order⬆⬆ Y387_Y417 0 P
Dephosphorylation of Syk

Syk(Y525_Y526~P) -> Syk(Y525_Y526~0)

Syk tSH2 Y525_Y526 0 P take one or more branches, once each, in any order⬆⬆