Protein tyrosine phosphatase receptor type gamma (PTPRG) is a JAK phosphatase and negatively regulates leukocyte integrin activation

Regulation of signal transduction networks depends on protein kinase and phosphatase activities. Protein tyrosine kinases of the JAK family have been shown to regulate integrin affinity modulation by chemokines and mediated homing to secondary lymphoid organs of human T-lymphocytes. However, the role of protein tyrosine phosphatases in leukocyte recruitment is still elusive. Here we address this issue by focusing on protein tyrosine phosphatase, receptor type γ (PTPRG), a tyrosine phosphatase highly expressed in human primary monocytes. We developed a novel methodology to study the signaling role of receptor type tyrosine phosphatases and found that activated PTPRG blocks chemoattractant-induced β2 integrin activation. Specifically, triggering of LFA-1 to high affinity state is prevented by PTPRG activation. High-throughput phospho-proteomics and computational analyses show that PTPRG activation affects the phosphorylation state of at least 31 signaling proteins. Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 de-phosphorylation on the critical 1007-1008 phosphotyrosine residues, implying JAK2 inhibition and, thus, explaining the anti-adhesive role of PTPRG. Overall, the data validate a new approach to study receptor tyrosine phosphatases and show that, by targeting JAKs, PTPRG down-modulates the rapid activation of integrin affinity in human monocytes, thus emerging as a potential novel critical regulator of leukocyte trafficking.