Regulation, targets and functions of CSK

Abstract

The Src family kinases (SFK) plays an important role in multiple signal transduction pathways. Aberrant activation of SFKs leads to diseases such as cancer, blood disorders, and bone pathologies. By phosphorylating and inactivating SFKs, the C-terminal Src kinase (CSK) serves as the key negative regulator of SFKs. Similar to Src, CSK is composed of SH3, SH2, and a catalytic kinase domain. However, while the Src kinase domain is intrinsically active, the CSK kinase domain is intrinsically inactive. Multiple lines of evidence indicate that CSK is involved in various physiological processes including DNA repair, permeability of intestinal epithelial cells (IECs), synaptic activity, astrocyte-to-neuron communication, erythropoiesis, platelet homeostasis, mast cell activation, immune and inflammation responses. As a result, dysregulation of CSK may lead to many diseases with different underlying molecular mechanisms. Furthermore, recent findings suggest that in addition to the well-established CSK-SFK axis, novel CSK-related targets and modes of CSK regulation also exist. This review focuses on the recent progress in this field for an up-to-date understanding of CSK.

Keywords: Chk; Csk; SFK; activity; regulation; src; target.

FIGURE 1

Regulation and molecular targets of CSK. SFKs in the lipid rafts phosphorylate CBP/PAG-1 and other CSK binding proteins (caveolin-1, Dok-1, Dok-2, etc.), which activate and recruit CSK (via SH2 of CSK) to the lipid rafts where SFKs are enriched. CSK phosphorylates SFKs at its Y530, causing inactivation of SFKs. By recruiting protein tyrosine phosphatases (PTPs) via its SH3 domain, CSK also recruits the phosphatases to dephosphorylate and activate SFKs. Activated SFKs can be degraded by Cbl-family mediated-ubiquitination and degradation. SFKs are also likely brought closer to CBP/CSK complex by Thy-1 to be inactivated. Both TRAF3 and PIAS3 negatively modulate the tumor suppressor function of CSK. TRAF3 dissociates CSK and PTP from SFKs. PIAS3 reduces CSK/CBP interaction by SUMOylating CSK. PKA phosphorylates CSK at Ser364 to make CSK more kinase active. CDC42 kinase 1 (ACK1) also activates CSK via phosphorylation of CSK at Y18. ELTD1 can interact with and lower the level of CSK. Upon DNA virus infection, CSK phosphorylates MITA at its Y240 and Y245, to activate MITA to promote innate antiviral response. When CSK levels are elevated, via a Src-independent mechanism(s), overexpression of tricellular junction (TCJ) protein gliotactin are decreased by increased endocytosis of gliotactin. Loss of gliotactin usually results in breakdown of the TCJs, leading to the loss of the barrier function.

FIGURE 2

Functions of CSK. Via SFK, CSK is involved in permeability of IECs, erythropoiesis, synaptic activity, blood pressure, platelet homeostasis, mast cell activation, immune response and inflammation including TLR, TCR and BCR astrocyte-to-neuron communication, DNA repair, and cancer.