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This version published online on August 14, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0256
Molecular Endocrinology Vol. 0, No. 2003 200302561-
doi:10.1210/me.2003-0256
Copyright © 2003 by the Endocrine Society.
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Submitted on June 27, 2003
Accepted on August 5, 2003

JAK2 Determinants for GH Receptor Association, Surface Assembly, and Signaling

Kai He1, Xiangdong Wang1, Jing Jiang1, Ran Guan1, Kenneth E. Bernstein1, Peter P. Sayeski1, and Stuart J. Frank1*

1 Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, and Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL; Department of Pathology, Emory University School of Medicine, Atlanta, GA; Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL; Endocrinology Section, Medical Service, Veterans Affairs Medical Center, Birmingham, AL

* To whom correspondence should be addressed. E-mail: sjfrank{at}uab.edu.

GH signaling depends on functional interaction of the GH receptor (GHR) and the cytoplasmic tyrosine kinase, JAK2, which possesses a C-terminal kinase domain, a catalytically-inactive pseudokinase domain just N-terminal to the kinase domain, and an N-terminal half shown by us and others to harbor elements for GHR association. Computational analyses indicate that JAKs contain in their N-termini (~450 residues) divergent FERM domains. FERM domains (or subdomains within them) in JAKS may be important for associations with cytokine receptors. For some cytokine receptors, JAK interaction may be required for receptor surface expression. We previously demonstrated that a JAK2 mutant devoid of its N-terminal 239 residues (JAK2-{Delta}1-239) did not associate with GHR and could not mediate GH-induced signaling. In this report, we employ a JAK2-deficient cell line to further define N-terminal JAK2 regions required for physical and functional association with the GHR. We also examine whether JAK2 expression affects cell surface expression of the GHR. Our results suggest that FERM motifs play an important role in the interaction of GHR and JAK2. While JAK2 expression is not required for detectable surface GHR expression, increased JAK2 level increases the fraction of GHRs that achieves resistance to deglycosylation by endoglycosidase H, suggesting that the GHR-JAK2 association may enhance either the receptor's efficiency of maturation or its stability. Further, we report evidence for the existence of a novel GH-inducible functional interaction between JAK2 molecules that may be important in the mechanism of GH-triggered JAK2 signaling.




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