SHP-2 Binds to Caveolin-1 and Regulates Src Activity via Competitive Inhibition of Csk in Response to H2O2 in Astrocytes

Abstract

Reactive oxygen species (ROS) regulate diverse cellular functions by triggering signal transduction events, such as Src and mitogen-activated protein (MAP) kinases. Here, we report the role of caveolin-1 and Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2) in H 2 O 2 -induced signaling pathway in brain astrocytes. H 2 O 2 -mediated oxidative stress induced phosphorylation of caveolin-1 and association between p-caveolin-1 and SHP-2. SHP-2 specifically bound to wild-type caveolin-1 similarly to c-Src tyrosine kinase (CSK), but not to phosphorylation-deficient mutant of caveolin-1 (Y14A), and interfered with complex formation between caveolin-1 and CSK. In the presence of CSK siRNA, binding between caveolin-1 and SHP-2 was enhanced by H 2 O 2 treatment, which led to reduced Src phosphorylation at tyrosine (Tyr) 530 and enhanced Src phosphorylation at Tyr 419. In contrast, siRNA targeting of SHP-2 facilitated H 2 O 2 -mediated interaction between caveolin-1 and CSK and enhanced Src phosphorylation at Tyr 530, leading to subsequent decrease in Src downstream signaling, such as focal adhesion kinase (FAK) and extracellular signal-related kinase (ERK). Our results collectively indicate that SHP-2 alters Src kinase activity by interfering with the complex formation between CSK and phosphotyrosine caveolin-1 in the presence of H 2 O 2 , thus functions as a positive regulator in Src signaling under oxidative stress in brain astrocytes.

Involvement of caveolin-1 in neurovascular unit remodeling after stroke: Effects on neovascularization and astrogliosis

“…Although several studies investigated Cav-1 signaling pathways of astrocytes in vitro , 40–42 the mechanism by which Cav-1 regulates astrogliosis is still unclear. In an OGD-R in vitro model, a recent study suggested that basic fibroblast growth factor (bFGF) might protect astrocytes from injury by up regulating the Cav-1/VEGF signaling pathway 42 indicating in addition to its roles in neovascularization and neurogenesis, this pathway may be involved in astrogliosis, astroglial scar formation and neuroinflammation after cerebral ischemia.…”

The non-receptor tyrosine phosphatase type 14 blocks caveolin-1-enhanced cancer cell metastasis

“…CAV1 is subjected to post-translational modifications relevant to protein function, such as phosphorylation on tyrosine-14 (pY14) by the non-receptor protein tyrosine kinases Src, Fyn, and Abl. This may occur in response to a large variety of stimuli, such as insulin, ultraviolet radiation, hydrogen peroxide, hyperosmolarity, and hemodynamic shear stress [15][16][17][18][19][20][21][22][23]. Upon Y14 phosphorylation, CAV1 binds to and inactivates the C-terminal Src kinase (Csk), thereby increasing Src activity [24], which is required for CAV1 to enhance cell migration [4,[25][26][27][28].…”

Upregulated SHP‐2 expression in the epileptogenic zone of temporal lobe epilepsy and various effects of SHP099 treatment on a pilocarpine model

“…Furthermore, SHP-2 is an appealing molecule in the context of the regulation of neurogenesis and gliogenesis (7,23). Recently, SHP-2 was found to participate in many important physiological and pathological processes, including the regulation of synaptic plasticity (27,30), neurite outgrowth (11,41), neuronal excitotoxicity (42), neuronal death (13) and oxidative stress (21). Notably, these processes are also critical for the occurrence and development of temporal lobe epilepsy.…”