Apoptosis regulation by the tyrosine-protein kinase CSK

Abstract

C-terminal Src kinase (CSK) is a cytosolic tyrosine-protein kinase with an important role in regulating critical cellular decisions, such as cellular apoptosis, survival, proliferation, cytoskeletal organization and many others. Current knowledge on the CSK mechanisms of action, regulation and functions is still at an early stage, most of CSK's known actions and functions being mediated by the negative regulation of the SRC family of tyrosine kinases (SFKs) through phosphorylation. As SFKs play a vital role in apoptosis, cell proliferation and survival regulation, SFK inhibition by CSK has a pro-apoptotic effect, which is mediated by the inhibition of cellular signaling cascades controlled by SFKs, such as the MAPK/ERK, STAT3 and PI3K/AKT signaling pathways. Abnormal functioning of CSK and SFK activation can lead to diseases such as cancer, cardiovascular and neurological manifestations. This review describes apoptosis regulation by CSK, CSK inhibition of the SFKs and further explores the clinical relevance of CSK in important pathologies, such as cancer, autoimmune, autoinflammatory, neurologic diseases, hypertension and HIV/AIDS.

Keywords: Csk; MAPK pathway; PI3K-Akt pathway; SFK; Src kinases; apoptosis; src; tyrosine-protein kinase CSK.

FIGURE 1

Comparison of CSK and SFK structure. CSK (left) and SFK (right) structures are illustrated, showing the configuration of the respective domains of the two molecules. Here, c-Src is used as a representative for SFKs. The hollows indicate binding sites in the SH2 and SH3 domain. The light blue SH2 domain of CSK (left) represents its location in an active state of the CSK molecule, whereas the pink SH2 domain shows SH2 domain position in an inactive molecule. The red dot in the C-terminal domain of c-Src (right) shows the C-terminal regulatory tyrosine (Tyr-527) where CSK phosphorylates c-Src in order to inhibit c-Src. Adapted from Reference (Ogawa et al., 2002), with permission, under the Creative Commons Attribution (CC BY 4.0) License.

FIGURE 2

CSK-mediated inactivation of substrate kinases (SFKs) through phosphorylation. The substrates of CSK, Src proteins (SFKs), are composed of three domains (SH1, SH2 and SH3), with an additional SH4 domain situated on the N-terminal region, which has an important role in attaching Src to the cell membrane (Kim et al., 2009). SH1 is the catalytic domain responsible for the tyrosine kinase activity of Src, while SH2 and SH3 can interact with other signaling proteins. The regulation of Src activity is ensured through phosphorylation and dephosphorylation of a C-terminal tyrosine residue (Y530) (Chen et al., 2014). The active form (on the left) is able to bind substrates while Y530 is not phosphorylated. When the C-terminal Src kinase (CSK) phosphorylates Y530, the conformation of Src changes and it becomes unable to bind substrates and exert its tyrosine kinase activity (the inactive form, shown on the right) (Reinehr et al., 2013; Ortiz et al., 2021). Created with BioRender.com.

FIGURE 3

Cellular functions regulated by CSK through inhibition of SFK signaling pathways. Src family proteins (SFKs) are involved in a multitude of signaling pathways, mostly responsible for cell proliferation (e.g. MAPK/ERK, STAT3, PI3K/AKT pathways), angiogenesis (e.g., VEGF, IL-8) and cytoskeletal reorganization. Through phosphorylation (as seen on the left), CSK is able to inactivate SFKs, thus exerting an inhibitory effect on all the pathways in which the latter is involved (represented on the right). The main results are: promoting apoptosis (as opposed to cell proliferation), inhibition of angiogenesis, interrupting the pro-oncogenic effects of SFK such as cancer cell migration and invasion, while also interfering with cytoskeletal reorganization (Kim et al., 2009; Chen et al., 2014). Created with BioRender.com.

FIGURE 4

CSK regulation of apoptosis. CSK inhibits MAPK/ERK, STAT3 and PI3K/AKT signaling pathways, which are normally involved in promoting cell proliferation and/or survival, through regulation of transcription factors in the nucleus, thus preventing their augmentative effects on cell growth and promoting apoptosis. CSK could potentially promote apoptosis through activation of Forkhead box, subclass O (FOXO) proteins, which are usually inactivated by AKT when the PI3K/AKT pathway is active. FOXO has upregulating and downregulating effects on many transcription factors, ultimately promoting apoptosis (Dumitrascu and Bucur, 2013; Fang et al., 2013; Bucur et al., 2014; Chen et al., 2014; Guo et al., 2020; Ma et al., 2020; Vidal et al., 2021). Created with BioRender.com.