The Interaction between Cancer Stem Cell Marker CD133 and Src Protein Promotes Focal Adhesion Kinase (FAK) Phosphorylation and Cell Migration

Abstract

CD133, a widely known cancer stem cell marker, has been proved to promote tumor metastasis. However, the mechanism by which CD133 regulates metastasis remains largely unknown. Here, we report that CD133 knockdown inhibits cancer cell migration, and CD133 overexpression promotes cell migration. CD133 expression is beneficial to activate the Src-focal adhesion kinase (FAK) signaling pathway. Further studies show that CD133 could interact with Src, and the region between amino acids 845 and 857 in the CD133 C-terminal domain is indispensable for its interaction with Src. The interaction activates Src to phosphorylate its substrate FAK and to promote cell migration. Likewise, a Src binding-deficient CD133 mutant loses the abilities to increase Src and FAK phosphorylation and to promote cell migration. Inhibition of Src activity by PP2, a known Src activity inhibitor, could block the activation of FAK phosphorylation and cell migration induced by CD133. In summary, our data suggest that activation of FAK by the interaction between CD133 and Src promotes cell migration, providing clues to understand the migratory mechanism of CD133 ؉ tumor cells.Tumor metastasis is a process by which tumor cells detach from the primary tumor into the stroma and invade blood vessels. This is followed by a secondary tumor growth at a distant site (1). This accounts for over 90% of lethality in cancer patients (2). Increasing evidence indicates that there is a subset of tumor cells contributing to metastasis that has properties of cancer stem cells (3). CD133, a pentaspan transmembrane glycoprotein, has rapidly gained clinical value with its wide use as a cancer stem cell marker (4 -13). A series of studies have shown that CD133 could directly regulate tumorigenesis, cell self-renewal, and angiogenesis (14 -16). Increasing evidence has also shown that CD133 is related to tumor metastasis in a variety of solid tumors (17)(18)(19)(20). For instance, activation of AKT/protein kinase B (PKB) signal pathway promotes invasion and migration of CD133 ϩ cancer stem cells in brain cancer (21). G protein-coupled receptor 87 was found to promote the growth and metastasis of CD133 ϩ cancer stem cells in hepatocellular carcinoma. CD133 expression is correlated with lymph node metastasis in pancreatic cancer (22,23). However, the mechanisms of CD133 regulating metastasis directly remain largely unknown.In head and neck cancer, CD133 could regulate Src kinase activity. The CD133/Src axis mediates tumor-initiating property and epithelial mesenchymal transition (24). Src is a member of the Src family of kinases, which is a non-receptor tyrosine kinase family (25,26). Src is highly expressed or highly activated in various human cancers (27). For instance, Src is highly active in glioblastoma multiforme specimens, and it represents an effective target for CD133 ϩ glioblastoma multiforme stem cell migration (28). Among the kinase substrates of Src, FAK 4 is an important mediator of tumor progressions and metastasis through the modulation of tumor cell migrat...

Prominin‐1 (CD133) modulates the architecture and dynamics of microvilli

“…Their regulation by certain subunits of Arp2/3 complex, notably p34‐Arc/ARPC2 and vinculin, has been proposed . Similarly, Liu et al have demonstrated that the interaction of prominin‐1 with Src protein promotes the phosphorylation of focal adhesion kinase and cancer cell migration …”

CD133 as a regulator of cancer metastasis through the cancer stem cells

“…It suggested a role of CD133 in the initiation of colon cancer metastasis. Knockdown of CD133 in SW620 human colon cancer cells impaired cell migration through reduced phosphorylations of Src-focal adhesion kinase (FAK) and this is due to a failure of forming a complex of CD133, Src, and FAK (Liu et al, 2016). Furthermore, the interaction between CD133 and Src is required for CD133-induced cell motility by activation of Src downstream target FAK.…”

Complex N‐glycan promotes CD133 mono‐ubiquitination and secretion

“…The interaction between phosphorylated CD133 (Y828 residue) and the PI3K regulatory subunit p85 activates PI3K/Akt pathway to promote tumorigenesis in glioma stem cells [8]. In addition, interaction between the C-terminal domain of CD133 and Src enhances the phosphorylation of FAK and promotes tumor cell migration [9]. These observations imply the critical role of CD133 in tumor initiation and metastasis.…”

“…Existing evidence suggests that interaction of CD133 and VEGF promotes tumor growth by supporting angiogenesis [7]. In addition, interaction between the C-terminal domain of CD133 and Src enhances the phosphorylation of FAK and promotes tumor cell migration [9]. In addition, interaction between the C-terminal domain of CD133 and Src enhances the phosphorylation of FAK and promotes tumor cell migration [9].…”