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Socs1 binds to multiple signalling proteins and suppresses Steel factor‐dependent proliferation
Author(s) -
Sepulveda Paulo De,
Okkenhaug Klaus,
Rose Jose La,
Hawley Robert G.,
Dubreuil Patrice,
Rottapel Robert
Publication year - 1999
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/18.4.904
Subject(s) - suppressor of cytokine signaling 1 , biology , proto oncogene tyrosine protein kinase src , microbiology and biotechnology , janus kinase , sh2 domain , tyrosine kinase , suppressor of cytokine signalling , receptor tyrosine kinase , signal transduction , socs3 , biochemistry , stat3 , suppressor , gene
We have identified Socs1 as a downstream component of the Kit receptor tyrosine kinase signalling pathway. We show that the expression of Socs1 mRNA is rapidly increased in primary bone marrow‐derived mast cells following exposure to Steel factor, and Socs1 inducibly binds to the Kit receptor tyrosine kinase via its Src homology 2 (SH2) domain. Previous studies have shown that Socs1 suppresses cytokine‐mediated differentiation in M1 cells inhibiting Janus family kinases. In contrast, constitutive expression of Socs1 suppresses the mitogenic potential of Kit while maintaining Steel factor‐dependent cell survival signals. Unlike Janus kinases, Socs1 does not inhibit the catalytic activity of the Kit tyrosine kinase. In order to define the mechanism by which Socs1‐mediated suppression of Kit‐dependent mitogenesis occurs, we demonstrate that Socs1 binds to the signalling proteins Grb‐2 and the Rho‐family guanine nucleotide exchange factors Vav. We show that Grb2 binds Socs1 via its SH3 domains to putative diproline determinants located in the N‐terminus of Socs1, and Socs1 binds to the N‐terminal regulatory region of Vav. These data suggest that Socs1 is an inducible switch which modulates proliferative signals in favour of cell survival signals and functions as an adaptor protein in receptor tyrosine kinase signalling pathways.