Regulation of FAK Activity by Tetraspan Proteins: Potential Clinical Implications in Cancer

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that regulates multiple cell signaling pathways in both physiological and pathological conditions. Overexpression and activation of FAK is associated with many advanced stage cancers through promoting cancer cell tumorigenicity and progression as well as by regulating the tumor microenvironment. FAK has multiple binding partners through which FAK exerts its functions including RhoGEF, Src family, talin, cortactin, and paxilin. Over the last few years, it has been proposed that a novel group of four transmembrane proteins can interact with FAK and regulate its activity. These include select tetraspanins such as CD151 and CD9 as well as the GAS3 family members epithelial membrane protein-2 (EMP2) and peripheral myelin protein-22 (PMP22). In this review, we discuss the current knowledge of the interaction between FAK and tetraspan proteins in physiological and pathological conditions, with an emphasis on the potential of tetraspan family members as therapeutic targets in cancer.

Combinatorial Inhibition of Focal Adhesion Kinase and BCL-2 Enhances Antileukemia Activity of Venetoclax in Acute Myeloid Leukemia

“…Focal adhesion kinase (FAK) is frequently activated or overexpressed in cancer cells (1). FAK activation is initiated through autophosphorylation at Y397, resulting in SRC phosphorylation and formation of the FAK/SRC complex, which leads to phosphorylation of other tyrosine sites and full activation of FAK (2). Activated FAK modulates multiple signaling pathways, including PI3K/AKT and MAPK, to promote cell growth, survival, migration, and tumor metastasis (1).…”

Astrocyte focal adhesion kinase reduces passive stress coping by inhibiting ciliary neurotrophic factor only in female mice

“…CUS reduces the expression of connexin 43 in the rodent prefrontal cortex ( Giaume et al, 2010 ; Miguel-Hidalgo et al, 2018 ; Sun et al, 2012 ). In glioma stem cells and some cancer models, connexin 43 directly interacts with FAK ( Tien et al, 2021 ; Zhou et al, 2020 ) and regulates FAK activity by recruiting Src, Src inhibitors, as well as phosphatase and tensin homolog ( Jaraiz-Rodriguez et al, 2017 ; Qin et al, 2015 ). Stress also induces extensive extracellular matrix (ECM) remodeling and modulates integrin expression and function, possibly by stimulating ECM-degrading enzyme, leading to reduced integrin binding ( Jean et al, 2011 ).…”

Microdomain forming proteins in oncogenesis

“…В опытах с ксенографтами глиобластом человека показано, что разрушение таких комплексов приводит к снижению уровня активации EGFR, FAK и малых GTPаз, что, в свою очередь, увеличивает сроки жизни мышей-опухоленосителей [64]. Следует отметить, что FAK может напрямую связываться с тетраспанинами CD151 и CD9 [65].…”

“…7) [68], дан-ные результаты вполне закономерны, а его протуморо-генные и прометастатические функции вполне очевидны. Об этом же свидетельствует тот факт, что моноклональ-ные антитела CD151 mAb 9B, диссоциирующие ком-плекс α6β1 с экстраклеточным доменом СD151, ингиби-руют ангиогенез, подвижность и инвазивность клеток, что дает возможность рассматривать ингибиторы CD151 в качестве терапевтических агентов [59,65,68].…”