CD99 inhibits CD98-mediated β1 integrin signaling through SHP2-mediated FAK dephosphorylation

CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of β1 Integrin through the Protein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway

“…In this study, we showed that CD99-derived agonistic ligands function as novel suppres- sors of fibronectin-mediated ␤1 integrin activation in human breast carcinoma cells and uncovered for the first time the underlying mechanism by which CD99 regulates ␤1 integrin activity. This study is consistent with our previous study showing that antibody-mediated cross-linking of CD99 suppresses the mechanisms of ␤1 integrin activation by CD98 or ECMs such as collagen, fibronectin, and laminin (33). In addition, the activation of CD99 itself led to the activation of PKA and the subsequent recruitment of SHP2, resulting in the activation of the HRAS/MAPK signaling pathway.…”

“…It has been implicated in the regulation of focal adhesion disassembly and cell motility by regulating the dephosphorylation of several protein kinases and signaling molecules. Previously, we demonstrated the role of another cytosolic phosphatase, SHP2, in FAK dephosphorylation, but whether SHP2 dephosphorylates FAK directly or indirectly remains unknown (33). Our results showed that PTPN12 physically interacts with FAK, unlike SHP2, suggesting that PTPN12 directly contacts FAK and facilitates its dephosphorylation at Y397, whereas SHP2 is indirectly involved in the dephosphorylation of FAK by triggering the HRAS/MAPK signaling pathway.…”

“…It is well known that SHP2 operates in integrin signaling and adhesion site dynamics by regulating FAK phosphorylation (39,40). In addition, we previously reported that crosslinking of CD99 with an anti-CD99 MAb led to SHP2 recruitment, followed by FAK dephosphorylation at tyrosine 397 and ␤1 integrin inactivation (33). To determine whether SHP2 is engaged in the suppression of ␤1 integrin activity caused by CD99 (Continued on next page) CD99 Agonist Ligands Suppress ␤1 Integrin Activity Molecular and Cellular Biology peptide treatment, MCF-7 cells were transfected with a SHP2 small interfering RNA (siRNA) (Fig.…”

“…Our previous results showed that cross-linking of CD99 with an anti-CD99 MAb suppresses ␤1 integrin activity (33,34). Because CD99 interacts homophilically through its N-terminal extracellular domain (24,25,35), we tried to determine whether, similarly to the anti-CD99 MAb, CD99-derived agonist ligands could modulate ␤1 integrin activity.…”

“…In addition, CD99 inhibits tumor metastasis through the suppression of C-SRC and ROCK2 activities in osteosarcoma (30)(31)(32). Notably, we reported that CD99 engagement blocks CD98-mediated ␤1 integrin signaling, which could suppress tumor progression by inhibiting a positive feedback loop of CD98/␤1 integrin/focal adhesion kinase (FAK)/RHOA/ROCK (33).…”