Cytokine Receptor Signal Transduction and Regulation of Cell Growth

The growth of myeloid and lymphoid blood cells is governed by cytokine growth factors acting through Type I cytokine receptors. This receptor family functions through activation of Jak tyrosine kinases, which phosphorylate components of signaling pathways controlling cell survival and proliferation. Blood cell development fails in the absence of Jak kinase activation resulting in anemias, whereas enhanced Jak kinase activity contributes to myeloid and lymphoid leukemias. Work in our laboratory is directed at defining mechanism by which cytokines regulated blood cell growth.
Proper regulation of Jak kinase activity requires mechanisms controlling activation of the kinase that are balanced against mechanisms controlling its inactivation. Mechanisms inhibiting Jak kinase activity include its degradation, which is governed by ubiquitination mediated by SOCS proteins. We have shown that Jak kinases and cytokine receptors can also be ubiquitinated by a receptor-associated ubiquitin ligase, RUL. Inhibition of RUL activity limits the ability of cytokines to induce Jak-dependent phosphorylation of signaling proteins and inhibits cell growth, suggesting that Jak activity is enhanced by RUL-mediated ubiquitin ligation. The finding that RUL-mediated ubiquitination is required for Jak signaling is novel, and forms the basis for our hypothesis that different mediators of Jak ubiquitination exert distinct influences on its kinase activity. Thus, a major focus of work in our laboratory is to define the role of RUL in regulating Jak kinase activity, and test the concept that competing ubiquitination between a promoter (e.g., RUL) and inhibitor (e.g., SOCS1) regulates the activity of Jak kinases in vivo. This concept represents a novel paradigm in the regulation of signal transduction by mediators of ubiquitination, and as such broadens the potential impact of this work toward receptor signaling in general
The lack of proliferation by hematopoietic cells deprived of cytokine is associated with their accumulation in G1 phase of the cell cycle. This implies a direct link between the activities of cytokine receptors and regulators of cell cycle progression. However the specific roles of signaling pathways activated by cytokine receptors in promoting G1 phase progression has not been clearly defined. We have shown that cytokine-treatment overrides G1 and G2/M phase growth arrest in hematopoietic cells exposed to DNA damaging agents. Blockade of these growth arrest checkpoints is dependent on activation of phosphoinositide 3-kinase (PI3K) signaling pathways, and correlates with the appearance of a Cdk2 activating kinase (CAK) activity in lysates of irradiated cells. These observations define a signaling pathway connecting cytokine-induced PI3K and regulated Cdk2 activity in hematopoietic cells. Thus a second focus of work in our laboratory is to define the molecular mechanisms that govern this PI3K-mediated signaling pathway, and ultimately to determine the general parameters required for cytokine-dependent blockade of DNA damage checkpoints. These studies will advance our fundamental understanding of cytokine signaling pathways, and will help to establish important paradigms of cell cycle regulation, DNA damage checkpoints, and their regulation by extracellular signals.

Representative Publications:

Chakravarti, P., Henry, M.K., Quelle, F.W.: Prolactin and heregulin override DNA damage-induced growth arrest and promote phosphatidylinositol-3 kinase-dependent proliferation in breast cancer cells. Int J Oncol. 26(2):509-14, 2005.

Henry, M.K., D. Nimbalkar, R.J. Hohl, F.W. Quelle. Cytokine-induced phosphoinositide 3-kinase activity promotes Cdk2 activation in factor-dependent hematopoietic cells. Experimental Cell Research, 299:257-266, 2004.

Friedman, A.D., D. Nimbalkar, F.W. Quelle. Erythropoietin receptors associate with a ubiquitin ligase, p33RUL, and require its activity for erythropoietin-induced proliferation. J. Biol. Chem, 29:26851-26861, 2003.

Nimbalkar, D., M.K. Henry , and F.W. Quelle. Cytokine activation of phosphoinositide 3-kinase sensitizes hematopoietic cells to cisplatin-induced death. Cancer Research, 63:1034-1039, 2003.

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Center and Program affiliations:

The Interdisciplinary Graduate Program in Immunology

Biosciences Program

The Diabetes and Endocrinology Research Center