Cbl-b promotes cell detachment via ubiquitination of focal adhesion kinase

Abstract

Abstract. Cancer cell detachment from the primary tumor site represents the first stage of metastasis. Previous studies have identified that cell detachment is triggered by cytoskeletal disruption, which may induce a wide variety of cellular changes. Focal adhesion kinase (FAK) exhibits crucial cellular functions, including regulation of the cytoskeleton. These observations have provided exciting insights into the effect of FAK in cell detachment; however, the involvement of FAK in cell detachment remains controversial. The aim of the present study was to evaluate the effect of FAK and its function in the process of cell detachment. The results revealed that FAK expression was downregulated following trypsin treatment in human gastric, lung, colon and breast cancer cell lines, as well as a human gastric epithelial cell line. Knockdown of FAK enhanced cell detachment in gastric cancer MGC803 cells, indicating that FAK inhibits cell detachment. Further investigation revealed that trypsin induced monoubiquitination of FAK. In addition, the lysosome inhibitor, NH 4 Cl, decreased trypsin-induced degradation of FAK. Casitas B-lineage lymphoma-b (Cbl-b), an E3 ubiquitin ligase, was involved in this process, which interacted with FAK, as demonstrated by co-precipitation experiments, and promoted trypsin-induced ubiquitin-lysosome degradation of FAK. These results indicate that Cbl-b promotes cell detachment via ubiquitination of FAK. These findings provide novel insights regarding the effect of FAK and Cbl-b in the process of cancer cell detachment.

Targeting of PFKFB3 with miR‐206 but not mir‐26b inhibits ovarian cancer cell proliferation and migration involving FAK downregulation

“…By contrast, in the same setting, transfection of miR-26b resulted in a glycolytic phenotype that fostered FAK activation and enhanced spontaneous migration by increasing GLUT1, despite a weak negative regulation of PFKFB3 protein levels. In line with the previous findings showing that FAK expression can be modulated at a post-translational level, 50,51 we hypothesize that miR-26b indirectly enhanced FAK as well as GLUT1 levels. However, we cannot exclude that miR-26b directly increased GLUT1 and FAK expression by upregulating 52 Remarkably, the PFKFB3 did not counteract the increased basal migration in miR-26b-overexpressing cells.…”

MicroRNA‑525 enhances chondrosarcoma malignancy by targeting F‑spondin 1

“…The upregulation of SPON1 can be transmitted to catalytic proteins, including FAK, which exerts broad effects on the signal transduction pathways downstream of integrins (29). As a cytosolic tyrosine kinase, autophosphorylated FAK directly interacts with another tyrosine kinase, Src, thus resulting in its phosphorylation and activation (30–32). Src signaling can further lead to the activation of PI3K/Akt signaling to modulate cancer cell proliferation and migration (33).…”

<p>Effects of Atypical Protein Kinase C Inhibitor (DNDA) on Lung Cancer Proliferation and Migration by PKC-ι/FAK Ubiquitination Through the Cbl-b Pathway</p>

“…In previous studies, the ubiquitination of FAK via Cbl-b resulted in cell detachment in gastric cancer MGC803 cells. 31 However, scientists have not yet investigated FAK ubiquitination via the Cbl-b pathway with PKC-ι involvement in NSCLC. In accordance with the IP data, we observed an association between FAK with Cbl-b ( Figure 7B and D).…”