Ian Hitchcock Ph.D
Department of Medicine
Stony Brook University
Stony Brook, NY 11794
Office telephone: 631-444-1901
All blood cell lineages originate from hematopoietic stem cells (HSCs) and their differentiation is tightly regulated by cytokines, transcription factors and cell-cell interactions. Our research focuses on the role of the hormone thrombopoietin (TPO), which promotes the survival and proliferation of HSCs as well as controlling megakaryocyte differentiation and the secondary signaling protein Janus kinase (JAK) 2. Previous studies have demonstrated that TPO binding to its receptor, c-Mpl, stimulates a number of downstream signaling pathways including JAK/STAT, PI3-K, PKC and MAPK. Consequently, aberrant TPO signaling can result in uncontrolled cell growth leading to hematopoietic malignancies, or in contrast, hematopoietic deficiencies including thrombocytopenia and aplastic anemia.
Our research focuses on the positive and negative regulation of TPO signaling, particularly the mechanisms that control TPO-mediated c-Mpl endocytosis and degradation to gain a better understanding of c-Mpl receptor cycling. We are also interested in finding novel protein-protein interactions that regulate c-Mpl signaling using a proteomic approach.
Recently, an activating mutation in JAK2 (JAK2V617F) was identified as being responsible for causing Philadelphia-negative myeloproliforative disease (MPDs). This mutation causes hyperporliforation in a number of hematopoietic progenitors, resulting in increased numbers of platelets, red blood cells and/or monocytes. The main cause of morbidity in MPD patients is cardiovascular disease and strokes as a result of increased thrombosis. By using novel transgenic models, we hope to identify the JAK2V617F-positive cellular components responsible for aberrant thormbosis and hemostasis in patients with MPDs
||Schematic representation of c-Mpl signaling following TPO stimulation. TPO binding to its cognate receptor c-Mpl causes a conformational of the receptor homodimer, bringing associated Janus kinase (JAK)2 proteins in closer juxtaposition, enabling their autophosphorylation. Activated JAK2 leads to phosphorylation and activation signal transducers and activators of transcription (STAT) proteins and phosphorylation of c-Mpl tyrosine residues. Phosphorylated c-Mpl residues act as docking sites for adaptor proteins including Src homology domain-containing transforming (SHC)-1, which associates with growth factor receptor-bound protein protein (GRB)2, and son of sevenless (SOS) to stimulate the mitogen-activated protein kinase (MAPK) signaling pathway via the proto-oncogene Ras. In addition, TPO stimulation of c-Mpl activates AKT via phosphinositide-3-kinase (PI-3K) and phosphatidylinositol (3,4,5) triphosphate, upregulating the forkhead box 01(FOX01) transcription factor.
- Kamala Bhavaraju, Parth R. Lakhani, Robert T. Dorsam, Jianguo Jin, Ian S. Hitchcock, Archana Sanjay, and Satya P. Kunapuli. G12/13 signaling pathways substitute for integrin αIIbβ3-independent thromboxane generation in platelets. PLoS One. 2011 Feb 10;6(2):e16586.
- Saur SJ, Sangkhae V, Geddis AE, Kaushansky K, Hitchcock IS. Ubiquitination and degradation of the thrombopoietin receptor c-Mpl. Blood. 2010; 115(6):1254-63.
- Fox NE, Chen R, Hitchcock IS, Keates-Baleeiro J, Frangoul H, Geddis AE. Compound heterozygous c-Mpl mutations in a child with congenital amegakaryocytic thrombocytopenia: functional characterization and a review of the literature.
Exp Hematol. 2009 Apr;37(4):495-503
- Hitchcock IS, Chen MM, King JR, Kaushansky K. YRRL motifs in the cytoplasmic domain of the thrombopoietin receptor regulate receptor internalization and degradation. Blood. 2008 Sep 15;112(6):2222-31.
- Hitchcock IS, Fox NE, Prevost N, Sear K, Sahttil SJ, Kaushansky K. Focal Adhesion Kinase in megakaryopoiesis: A study of megakaryocyte-specific FAK deletion. Blood, 2008 Jan 15;111(2):596-604.
- Hitchcock IS, Kaushansky K. Thrombopoietin promotes beta1-integrin-mediated adhesion in hematopoietic cells via the small GTPase Rap1. Exp Hematol. 2007 May;35(5):793-801.
Top of Page