Structure and function of jak3- SH2 domain

Abstract

Janus kinase 3 (Jak3) is a non-receptor tyrosine kinase expressed in hematopoietic and non-hematopoietic cells. Though expression of Jak3 is necessary for adaptive immune functions, non-hematopoietic cell expression of Jak3 is also essential for the regulation of several physiological functions of gastrointestinal mucosa. Both in immune cells and intestinal epithelial cells (IEC), Jak3 regulates cell migration and mucosal restitution respectively by cytoskeletal remodeling through interactions with actin binding proteins (ABPs). Jak3 also regulates chronic inflammation of gastrointestinal tract through intestinal differentiation, mucosal homeostasis, regulation of proliferation and apoptosis, and maintenance of mucosa barrier functions. Molecularly, these functions are regulated through posttranslational and transcriptional regulation of Jak3, ABPs, and adapter proteins p52ShcA. For all these functions of Jak3, tyrosine phosphorylation of the SH2 domain plays a central role not only during common gamma chain induced auto-phosphorylation of Jak3 but also during phosphatases mediated deactivation of Jak3. In this chapter, we discuss the intramolecular and trans-molecular switches that regulate Jak3 interactions with other proteins and several aspects of its functions. Since SH2 domain plays a central role not only in Jak3 functions but the functions of all non-receptor tyrosine kinases, last section of the chapter discusses SH2 domain as drug target for the amelioration of different chronic inflammatory and other diseases.