Current Research:

Growth hormone (GH) has long been recognized as the primary regulator of body growth and an important regulator of metabolism. Recombinant GH is now used therapeutically to promote growth in children with short-stature, increase the well-being of GH-deficient adults, increasethe rate of healing of burn patients, and prevent muscle wasting in AIDS and surgical patients. However, our understanding at the cellular and molecular level of how GH elicits its responses has been rudimentary, until recently. My laboratory is currently focused on delineating the signal transduction pathways at the cellular level by which GH elicits its diverse effects. We have shown that binding of GH to its cell surface receptor rapidly promotes the binding of the tyrosine kinase JAK2 to the GH receptor and activates JAK2. We have also identified a number of different signalling molecules that bind to GH receptor and/or JAK2, become tyrosyl phosphorylated and are activated in response to GH. These signalling molecules include: 1) Stat transcription factors, including Stats 1,3, 5a and 5b, involved in the regulation of gene transcription by GH; 2) Shc proteins whose phosphorylation leads to the activation of Ras and MAP kinase, proteins implicated in the regulation of cellular growth and/or differentiation; 3) insulin receptor substrates (IRS) 1 and 2, which are thought to be responsible for insulin-like metabolic effects of GH; 4) signal regulatory proteins (SIRPs) which are integrin associated protein receptors that appear to be negative regulators of GH action; and 5) SHP2 tyrosine phosphatase which may dephosphorylate GH receptors.

We are currently combining recombinant DNA techniques with immunological and biochemical approaches and cell imaging techniques to delineate the molecular mechanism by which GH activates JAK2 kinase, JAK2 kinase is subsequently inactivated, JAK2 initiates known signalling pathways, and the physiological responses to GH that utilize these pathways. Peptide screening of expression libraries and the yeast 2 hybrid system are being used to identify new signaling molecules that bind to the GH receptor and/or JAK2. Because GH receptor is a member of the recently described hematopoietin/cytokine family of receptors, all of which bind and activate JAK kinases, the insight we obtain with GH receptor signalling also provides insight into signalling pathways used by a large number of ligands with known or potential application in the treatment of a variety of diseases, including cancer and multiple sclerosis. One of the proteins under intensive investigation in our laboratory is SH2-B, a putative adapter protein we have shown to bind to JAK2 in response to GH, to be tyrosyl phosphorylated in response to GH and to be a potent activator of JAK2. SH2-B also regulates the actin cytoskeleton and cell motility. Finally we have shown SH2-B to be vital for nerve growth factor-dependent morphological differentiation of PC12 cells into neurons and cell survival. We are investigating the molecular basis for these latter functions and their relevance to diabetic neuropathy.

Representative Publications:

Argetsinger LS, Kouadio JL, Steen H, Stensballe A, Jensen ON, Carter-Su C.
Related Articles, Links. "Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity." Mol Cell Biol. 2004 Jun;24(11):4955-67. PMID: 15143187 [PubMed - indexed for MEDLINE]

Kurzer JH, Argetsinger LS, Zhou YJ, Kouadio JL, O'Shea JJ, Carter-Su C.
Related Articles, Links. "Tyrosine 813 is a Site of JAK2 Autophosphorylation Critical for Activation of JAK2 by SH2-B Beta." Mol Cell Biol. 2004 May;24(10):4557-70. PMID: 15121872 [PubMed - indexed for MEDLINE]

Chen L, Carter-Su C. Related Articles, Links. "Adapter Protein SH2-B beta Undergoes Nucleocytoplasmic Shuttling: Implications for Nerve Growth Factor Induction of Neuronal Differentiation." Mol Cell Biol. 2004 May;24(9):3633-47. PMID: 15082760 [PubMed - indexed for MEDLINE]

Tang H, Macpherson P, Argetsinger LS, Cieslak D, Suhr ST, Carter-Su C, Goldman D. Related Articles, Links. "CaM Kinase II-Dependent Phosphorylation of Myogenin Contributes to Activity-Dependent Suppression of nAChR Gene Expression in Developing Rat Myotubes." Cell Signal. 2004 May;16(5):551-63. PMID: 14751541 [PubMed - indexed for MEDLINE]

Wang X, Chen L, Maures TJ, Herrington J, Carter-Su C. Related Articles, Links. "SH2-B is a Positive Regulator of Nerve Growth Factor-Mediated Activation of the Akt/Forkhead Pathway in PC12 Cells." J Biol Chem. 2004 Jan 2;279(1):133-41. Epub 2003 Oct 16. PMID: 14565960 [PubMed - indexed for MEDLINE]