ABSTRACT
To determine feasibility of implementation of a weight loss program for overweight Latinos with severe mental illness. In this quasi-experimental study, a 14-week behavioral weight loss course (extended) was implemented at one clinic. A one-time nutrition class (brief) was given at a sister clinic. Implementation feasibility was assessed by consent and participation rates. Weight was followed for 6 months. Consent rates were high [77 % (49/64) extended; 68 % (39/57) brief], and 88 % (43/49) of extended subjects participated and 88 % (38/43) completed follow-up. Weight loss did not differ between groups. A behavioral weight loss course is feasible to implement for this population.
Subject(s)
Behavior Therapy , Mental Disorders/ethnology , Overweight/therapy , Weight Loss/ethnology , Weight Reduction Programs/methods , Aged , Feasibility Studies , Female , Follow-Up Studies , Health Promotion , Hispanic or Latino/psychology , Hispanic or Latino/statistics & numerical data , Humans , Male , Mental Disorders/psychology , Middle Aged , New York , Outpatients/statistics & numerical data , Overweight/ethnology , Patient Education as Topic , Severity of Illness Index , Socioeconomic Factors , Treatment OutcomeABSTRACT
The leptin receptor, LRb, and other cytokine receptors are devoid of intrinsic enzymatic activity and rely upon the activity of constitutively associated Jak family tyrosine kinases to mediate intracellular signaling. In order to clarify mechanisms by which Jak2, the cognate LRb-associated Jak kinase, is regulated and mediates downstream signaling, we employed tandem mass spectroscopic analysis to identify phosphorylation sites on Jak2. We identified Ser523 as the first-described site of Jak2 serine phosphorylation and demonstrated that this site is phosphorylated on Jak2 from intact cells and mouse spleen. Ser523 was highly phosphorylated in HEK293 cells independently of LRb-Jak2 activation, suggesting a potential role for the phosphorylation of Ser523 in the regulation of LRb by other pathways. Indeed, mutation of Ser523 sensitized and prolonged signaling by Jak2 following activation by the intracellular domain of LRb. The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. Thus, the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling.
Subject(s)
Phosphoserine/metabolism , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Receptors, Cell Surface/metabolism , Signal Transduction , Animals , Enzyme Activation , Gene Expression Regulation, Enzymologic , Glutamic Acid/genetics , Humans , Janus Kinase 2 , Mass Spectrometry , Mice , Mutation/genetics , Phosphorylation , Protein-Tyrosine Kinases/chemistry , Proto-Oncogene Proteins/chemistry , Receptors, Cell Surface/antagonists & inhibitors , Receptors, Leptin , Substrate SpecificityABSTRACT
Jak family tyrosine kinases mediate signaling by cytokine receptors to regulate diverse biological processes. Although Jak2 and other Jak kinase family members are phosphorylated on numerous sites during cytokine signaling, the identity and function of most of these sites remains unknown. Using tandem mass spectroscopic analysis of activated Jak2 protein from intact cells, we identified Tyr(221) and Tyr(570) as novel sites of Jak2 phosphorylation. Phosphorylation of both sites was stimulated by cytokine treatment of cultured cells, and this stimulation required Jak2 kinase activity. While we observed no gross alteration of signaling upon mutation of Tyr(221), Tyr(570) lies within the inhibitory JH2 domain of Jak2, and mutation of this site (Jak2(Y570F)) results in constitutive Jak2-dependent signaling in the absence of cytokine stimulation and enhances and prolongs Jak2 activation during cytokine stimulation. Mutation of Tyr(570) does not alter the ability of SOCS3 to bind or inhibit Jak2, however. Thus, the phosphorylation of Tyr(570) in vivo inhibits Jak2-dependent signaling independently of SOCS3-mediated inhibition. This Tyr(570)-dependent mechanism of Jak2 inhibition likely represents an important mechanism by which cytokine function is regulated.
