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ShcA and Grb2 mediate polyoma middle T antigen‐induced endothelial transformation and Gab1 tyrosine phosphorylation
Author(s) -
Ong Siew Hwa,
Dilworth Stephen,
HauckSchmalenberger Ingrid,
Pawson Tony,
Kiefer Friedemann
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.22.6327
Subject(s) - sh2 domain , grb2 , proto oncogene tyrosine protein kinase src , tyrosine phosphorylation , biology , microbiology and biotechnology , phosphorylation , receptor tyrosine kinase , tyrosine , tyrosine kinase , signal transduction , cancer research , biochemistry
Middle T antigen (PymT) is the principal transforming component of polyomavirus, and rapidly induces hemangiomas in neonatal mice. PymT, a membrane‐associated scaffold, recruits and activates Src family tyrosine kinases, and, once tyrosine phosphorylated, binds proteins with PTB and SH2 domains such as ShcA, phosphatidylinositol 3‐kinase (PI3K) and phospholipase Cγ‐1 (PLCγ‐1). To explore the pathways required for endothelial transformation in vivo , we introduced PymT mutant forms into mice. PymT variants unable to bind PI3K and PLCγ‐1 directly induced hemangiomas similarly to wild type, but a mutant unable to bind ShcA was transformation compromised. Requirement for a ShcA PTB domain‐ binding site was suppressed by replacing this motif in PymT with YXN sequences, which bind the Grb2 SH2 domain upon phosphorylation. Surprisingly, PymT recruitment of ShcA and Grb2 correlated with PI3K activation. PymT mimics activated receptor tyrosine kinases by forming a ShcA—Grb2—Gab1 complex, thus inducing Gab1 tyrosine phosphorylation, which itself is associated with PI3K. Therefore, PymT activation of ShcA–Grb2 signaling is critical for endothelial transformation, and PymT can stimulate Grb2 signaling to both the MAP kinase and PI3K pathways.