Activation of c-Src and Fyn Kinases by Protein-tyrosine Phosphatase RPTPα Is Substrate-specific and Compatible with Lipid Raft Localization

Abstract

Src family tyrosine kinases (SFKs) function in multiple signaling pathways, raising the question of how appropriate regulation and substrate choice are achieved. SFK activity is modulated by several protein-tyrosine phosphatases, among which RPTP␣ and SHP2 are the best established. We studied how RPTP␣ affects substrate specificity and regulation of c-Src and Fyn in response to epidermal growth factor and platelet-derived growth factor. We find that RPTP␣, in a growth factor-specific manner, directs the specificity of these kinases toward a specific subset of SFK substrates, particularly the focal adhesion protein Paxillin and the lipid raft scaffolding protein Cbp/PAG. A significant fraction of RPTP␣ is present in lipid rafts, where its targets Fyn and Cbp/PAG reside, and growth factor-mediated SFK activation within this compartment is strictly dependent on RPTP␣. Forced concentration of RPTP␣ into lipid rafts is compatible with activation of Fyn. Finally, RPTP␣-induced phosphorylation of Paxillin and Cbp/PAG induces recruitment of the SFK inhibitory kinase Csk, indicative of negative feedback loops limiting SFK activation by RPTP␣. Our findings indicate that individual SFK-controlling PTPs play important and specific roles in dictating SFK substrate specificity and regulatory mechanism.

Protein-tyrosine Phosphatase-α and Src Functionally Link Focal Adhesions to the Endoplasmic Reticulum to Mediate Interleukin-1-induced Ca2+ Signaling

“…6B). These data are con- sistent with the observation that Src becomes activated via dephosphorylation of Tyr 529 during adhesion and spreading on a fibronectin substrate, and this activation is dependent on and mediated by PTP␣ (24,42). Further, in PTP␣ Ϫ/Ϫ cells, there was abundant phosphorylation of the inhibitory residues (Tyr 529 ) of Src that was unchanged after IL-1 treatment (Fig.…”

Aβ promotes VDAC1 channel dephosphorylation in neuronal lipid rafts. Relevance to the mechanisms of neurotoxicity in Alzheimer’s disease

“…Furthermore, PTPs may also participate in Ab translocation into lipid rafts. Thus, PTPs modulate in lipid rafts Fyn kinase, a member of Src tyrosine kinases family (Vacaresse et al, 2008). Fyn participates in oligomer Ab recruitment into these microdomains (Williamson et al, 2008).…”

Impaired Interferon‐γ Responses, Increased Interleukin‐17 Expression, and a Tumor Necrosis Factor–α Transcriptional Program in Invasive Aspergillosis

“…These included HoxA7/9 (B cell development) [16], Pou2f2 (transcriptional activator of immunoglobulin expression) [30], Ciapin1 (cytokine-induced apoptosis inhibitor) [31], E2f1/2 (transcriptional activator, cellular proliferation) [32], CD33 (monocyte cell adhesion molecule) [33], Stra13 (positive regulator of T cell activation) [34], Ms4a4b (CD20 homolog, T cell differentiation) [35], transcription factor E3/ EB (CD40 dependent CD4 T cell-dependent antibody production) [36], CXCR4 (lymphocyte chemotaxis) [37], Bap31 (MHC class 1 export) [38], CD22 (regulation of B cell signalling) [39], Ccl11 (Eotaxin 1, eosinophil recruitment) [40], CCR9 (mucosal lymphocyte recruitment) [41], C-src tyrosine kinase (T cell activation) [42], and FMS-like tyrosine kinase 4 (lymphatic development) [43]. This finding suggests that a key component of the early inflammatory response in IA is the activation of genes involved in lymphoproliferative responses.…”