Title: Adapter protein Shc regulates Janus kinase 3 phosphorylation Author:Mishra, Jayshree; Kumar, Narendra Subject:Apoptosis ; Janus Kinase (Jak) ; Nonreceptor Tyrosine Kinase (Nrtk) ; Phosphatase ; Protein Phosphatase ; Wound Healing ; Janus Kinase 3 -- Metabolism ; Shc Signaling Adaptor Proteins -- Metabolism Description:
Although constitutive activation of Janus kinase 3 (Jak3) leads to different cancers, the mechanism of trans-molecular regulation of Jak3 activation is not known. Previously we reported that Jak3 interactions with adapter protein p52ShcA (Shc) facilitate mucosal homeostasis. In this study, we characterize the structural determinants that regulate the interactions between Jak3 and Shc and demonstrate the trans-molecular mechanism of regulation of Jak3 activation by Shc. We show that Jak3 autophosphorylation was the rate-limiting step during Jak3 trans-phosphorylation of Shc where Jak3 directly phosphorylated two tyrosine residues in Src homology 2 (SH2) domain and one tyrosine residue each in calponin homology 1 (CH1) domain and phosphotyrosine interaction domain (PID) of Shc. Direct interactions between mutants of Jak3 and Shc showed that although FERM domain of Jak3 was sufficient for binding to Shc, CH1 and PID domains of Shc were responsible for binding to Jak3. Functionally Jak3 was...
Is part of:
The Journal of biological chemistry, 06 June 2014, Vol.289(23), pp.15951-6
1083-351X (E-ISSN); 24795043 Version (PMID); 10.1074/jbc.C113.527523 (DOI)
Janus kinase 3 regulates adherens junctions and epithelial mesenchymal transition through β-catenin
Mishra, Jayshree, Das, Jugal Kishore, Kumar, Narendra
The Journal of biological chemistry, 06 October 2017, Vol.292(40), pp.16406-16419
[Peer Reviewed Journal]
Title: Identification of molecular switch regulating interactions of Janus kinase 3 with cytoskeletal proteins Author:Mishra, Jayshree; Karanki, Satya Sridhar; Kumar, Narendra Subject:Gene Expression Regulation, Enzymologic ; Cytoskeleton -- Metabolism ; Janus Kinase 3 -- Metabolism Description:
Janus kinase 3 (Jak3) is a nonreceptor tyrosine kinase expressed in both hematopoietic and nonhematopoietic cells. Although mutations that abrogate Jak3 functions cause different immunological disorders, its constitutive activation leads to various types of cancer. Previously, we demonstrated that Jak3 interacted with actin-binding protein villin, thereby facilitating cytoskeletal remodeling and wound repair. In this study, we characterize the structural determinants that regulate the interactions between Jak3 and cytoskeletal proteins of the villin/gelsolin family. Functional reconstitution of kinase activity by recombinant full-length (wt) Jak3 using Jak3-wt or villin/gelsolin-wt as substrate showed that Jak3 autophosphorylation was the rate-limiting step during interactions between Jak3 and cytoskeletal proteins. Determination of kinetic parameters showed that phosphorylated (P) Jak3-wt binds to P-villin-wt with a dissociation constant (K(d)) of 23 nM and a Hill's coefficient of 3.7....
Is part of:
The Journal of biological chemistry, 30 November 2012, Vol.287(49), pp.41386-91
1083-351X (E-ISSN); 23012362 Version (PMID); 10.1074/jbc.C112.363507 (DOI)
Title: Role of Janus kinase 3 in mucosal differentiation and predisposition to colitis Author:Mishra, Jayshree; Verma, Raj K; Alpini, Gianfranco; Meng, Fanyin; Kumar, Narendra Subject:Colitis ; Differentiation ; Inflammatory Bowel Disease ; Innate Immunity ; Jak Kinase ; Β-Catenin ; Cell Differentiation ; Genetic Predisposition to Disease ; Colitis -- Enzymology ; Intestinal Mucosa -- Enzymology ; Janus Kinase 3 -- Metabolism Description:
Janus kinase 3 (Jak3) is a nonreceptor tyrosine kinase expressed in both hematopoietic and nonhematopoietic cells. Previously, we characterized the functions of Jak3 in cytoskeletal remodeling, epithelial wound healing, and mucosal homeostasis. However, the role of Jak3 in mucosal differentiation and inflammatory bowel disease was not known. In this report, we characterize the role of Jak3 in mucosal differentiation, basal colonic inflammation, and predisposition toward colitis. Using the Jak3 knock-out (KO) mouse model, we show that Jak3 is expressed in colonic mucosa of mice, and the loss of mucosal expression of Jak3 resulted in reduced expression of differentiation markers for the cells of both enterocytic and secretory lineages. Jak3 KO mice showed reduced expression of colonic villin, carbonic anhydrase, secretory mucin muc2, and increased basal colonic inflammation reflected by increased levels of pro-inflammatory cytokines IL-6 and IL-17A in colon along with increased colonic myeloperoxidase...
Is part of:
The Journal of biological chemistry, 01 November 2013, Vol.288(44), pp.31795-806
1083-351X (E-ISSN); 24045942 Version (PMID); 10.1074/jbc.M113.504126 (DOI)
Title: Role of Janus Kinase 3 in Predisposition to Obesity-associated Metabolic Syndrome Author:Mishra, Jayshree; Verma, Raj K; Alpini, Gianfranco; Meng, Fanyin; Kumar, Narendra Subject:Janus Kinase (Jak) ; Toll-Like Receptor 4 (Tlr4) ; Diabetes ; Inflammation ; Innate Immunity ; Metabolic Syndrome ; Janus Kinase 3 -- Metabolism ; Metabolic Syndrome -- Genetics ; Obesity -- Genetics Description:
Obesity, a worldwide epidemic, is a major risk factor for the development of metabolic syndrome (MetS) including diabetes and associated health complications. Recent studies indicate that chronic low-grade inflammation (CLGI) plays a key role in metabolic deterioration in the obese population. Previously, we reported that Jak3 was essential for mucosal differentiation and enhanced colonic barrier functions and its loss in mice resulted in basal CLGI and predisposition to DSS induced colitis. Since CLGI is associated with diabetes, obesity, and metabolic syndrome, present studies determined the role of Jak3 in development of such conditions. Our data show that loss of Jak3 resulted in increased body weight, basal systemic CLGI, compromised glycemic homeostasis, hyperinsulinemia, and early symptoms of liver steatosis. Lack of Jak3 also resulted in exaggerated symptoms of metabolic syndrome by western high-fat diet. Mechanistically, Jak3 was essential for reduced expression and activation...
Is part of:
The Journal of biological chemistry, 04 December 2015, Vol.290(49), pp.29301-12
1083-351X (E-ISSN); 26451047 Version (PMID); 10.1074/jbc.M115.670331 (DOI)
Title: The surgical atrial fibrillation ablation with concomitant coronary artery bypass grafting on the testing grounds of cost and 1-year mortality Author:Kumar, Narendra Description:
Surgical ablation (SA) for atrial fibrillation has been gaining prominence with evolution of better tools and techniques that are ultimately resulting in better success rates (1-3). SA and coronary artery bypass grafting (CABG) are considered as the gold standards in their respective domains for treatment of atrial fibrillation and multi vessel coronary artery disease. Currently, CABG remains the most commonly performed cardiac surgery and most SA are performed simultaneously with other cardiac procedures (4).
Is part of:
Annals of translational medicine, September 2017, Vol.5(17), pp.364
2305-5839 (ISSN); 28936458 Version (PMID); 10.21037/atm.2017.06.68 (DOI)