Regulation of Src Family Kinases by

Phosphorylation of caveolin is an ideal mechanism to recruit Csk to its substrates (the Src-family kinases) that are highly enriched in the caveolae. Csk is a negative regulator of Src-family kinases [92]. Csk phosphorylates Src-family kinases at an inhibitory tyrosine (Tyr527 in Src). When this residue is phosphorylated, it binds to the SH2 domain in the amino-terminus of the kinase, folding it into an inactive conformation (domain structure of Src-family kinases: SH3, SH2, kinase domain, regulatory tail with Csk phosphorylation site). The Src-family kinases can be reactivated either through dephosphorylation of this residue, or by displacement of the C-terminal tail by another phosphoprotein. However, the Src-family kinases are lipid-modified and localized to the plasma membrane, while Csk is largely free in the cytosol. Csk must be specifically targeted to its substrates in membranes via an SH2-domain-mediated interaction with a tyrosine-phosphorylated protein. In brain and lymphocytes, Csk is recruited to lipid rafts in the plasma membrane through binding to a transmembrane protein called Cbp that is constitutively phosphorylated on tyrosine [93,94]. Binding to phosphorylated Cbp also activates Csk. Phosphocaveolin also targets Csk to its substrates in the plasma membrane. Src-family kinases are highly enriched in caveolae, both through their lipid modifications and through direct binding to the "scaffolding domain" of the caveolins. Therefore, phosphocaveolin is an ideal targeting subunit for Csk. Significantly, caveolin phosphorylation is stimulated in response to extracellular signals. In contrast, Cbp is constitutively phosphorylated, and only transiently dephosphorylated in response to T-cell activation. Regulated phosphorylation of caveolin represents a novel mechanism for the regulation of Src-family kinases by extracellular signals through the recruitment and activation of Csk.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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