Abl-dependent tyrosine phosphorylation of Sos-1 mediates growth-factor-induced Rac activation

Abstract

The non-receptor tyrosine kinase Abl participates in receptor tyrosine kinase (RTK)-induced actin cytoskeleton remodelling, a signalling pathway in which the function of Rac is pivotal. More importantly, the activity of Rac is indispensable for the leukaemogenic ability of the BCR-Abl oncoprotein. Thus, Rac might function downstream of Abl and be activated by it. Here, we elucidate the molecular mechanisms through which Abl signals to Rac in RTK-activated pathways. We show that Sos-1, a dual guanine nucleotide-exchange factor (GEF), is phosphorylated on tyrosine, after activation of RTKs, in an Abl-dependent manner. Sos-1 and Abl interact in vivo, and Abl-induced tyrosine phosphorylation of Sos-1 is sufficient to elicit its Rac-GEF activity in vitro. Genetic or pharmacological interference with Abl (and the related kinase Arg) resulted in a marked decrease in Rac activation induced by physiological doses of growth factors. Thus, our data identify the molecular connections of a pathway RTKs-Abl-Sos-1-Rac that is involved in signal transduction and actin remodelling.

Abl tyrosine kinases regulate cell–cell adhesion through Rho GTPases

“…The mechanism by which Crk phosphorylation by Abl results in Rac activation may involve the recruitment of the Crk-binding protein DOCK180, a guanine nucleotide exchange factor (GEF) for Rac (37). Alternatively, Abl may activate Rac by phosphorylating Sos-1, which was reported to stimulate the Rac-GEF activity of Sos-1 (14).…”

“…The Abl kinases regulate a variety of cytoskeletal processes downstream of receptor tyrosine kinases and integrins (9)(10)(11)(12)(13)(14). We have shown that Abl kinases play a role in the regulation of intercellular signals at the neuromuscular junction (NMJ) and at sites of contact between invading bacterial pathogens and mammalian host cells (9,15).…”

VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2

“…It has been shown that several GEFs activate Rac1 in response to EGF and PDGF signaling [13,[23][24][25]. To determine which exchange factors activate Rac1 downstream of VEGF, we first investigated the endogenous expression of candidate Rac1 GEFs in endothelial cells.…”

Abl Tyrosine Kinase Regulates Endocytosis of the Epidermal Growth Factor Receptor

“…We and others have shown that endogenous Abl kinases are rapidly activated after EGFR stimulation (18 -20). Abl kinases are required for EGF-mediated membrane ruffling and Rac activation at physiological concentrations of the ligand (21). Moreover, the SH2 domains of Abl1 and Abl2 have been shown to bind with high affinity to the EGFR and other ErbB family members by interacting with multiple tyrosines on the phosphorylated receptors (19,22).…”