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

The human CD99 protein is a 32-kDa type I transmembrane glycoprotein, while CD98 is a disulfide-linked 125-kDa heterodimeric type II transmembrane glycoprotein. It has been previously shown that CD99 and CD98 oppositely regulate β1 integrin signaling, though the mechanisms by which this regulation occurs are not known. Our results revealed that antibody-mediated crosslinking of CD98 induced FAK phosphorylation at Y397 and facilitated the formation of the protein kinase Cα (PKCα)–syntenin-focal adhesion kinase (FAK), focal adhesions (FAs), and IPP–Akt1–syntenin complex, which mediates β1 integrin signaling. In contrast, crosslinking of CD99 disrupted the formation of the PKCα–syntenin–FAK complex as well as FA via FAK dephosphorylation. The CD99-induced dephosphorylation of FAK was apparently mediated by the recruitment of Src homology region 2 domain-containing phosphatase-2 (SHP2) to the plasma membrane and subsequent activation of its phosphatase activity. Further consequences of the activation of SHP2 included the disruption of FAK–talin and talin–β1 integrin interactions and attenuation in the formation of the IPP–Akt1–syntenin complex at the plasma membrane, which resulted in reduced cell–ECM adhesion. This report uncovers the molecular mechanisms underlying the inverse regulation of β1 integrin signaling by CD99 and CD98 and may provide a novel therapeutic approach to treat inflammation and cancer. •Inverse effects of CD99 and CD98 on regulation of β1 integrin signaling were studied.•CD98 mediates β1 integrin signaling by inducing FAK phosphorylation.•CD98 crosslinking helps form PKCα–syntenin–FAK, FAs, and IPP–Akt1–syntenin complex.•CD99 induces FAK dephosphorylation by recruiting SHP2.•CD99-mediated SHP2 activation attenuates CD98-mediated β1 integrin signaling.