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Blood, 1 March 2006, Vol. 107, No. 5, pp. 1864-1871.
Prepublished online as a Blood First Edition Paper on October 25, 2005; DOI 10.1182/blood-2005-06-2600.
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HEMATOPOIESIS
An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor
Judith Staerk,
Catherine Lacout,
Takeshi Sato,
Steven O. Smith,
William Vainchenker, and
Stefan N. Constantinescu
From the Ludwig Institute for Cancer Research, Brussels; the Christian de Duve Institute of Cellular Pathology and the Experimental Medicine (MEXP) Unit, Université catholique de Louvain, Brussels, Belgium; Institut Nationale de la Santé et de la Recherche Médicale (INSERM) U362, Institute Gustave Roussy, Villejuif, France; and the Center for Structural Biology, Department of Biochemistry and Cell Biology, State University of New York at Stony Brook.
Ligand binding to the thrombopoietin receptor (TpoR) is thought to impose a dimeric receptor conformation(s) leading to hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation. Unlike other cytokine receptors, such as the erythropoietin receptor, TpoR contains an amphipathic KWQFP motif at the junction between the transmembrane (TM) and cytoplasmic domains. We show here that a mutant TpoR ( 5TpoR), where this sequence was deleted, is constitutively active. In the absence of ligand, 5TpoR activates Jak2, Tyk2, STAT5, and mitogen-activated protein (MAP) kinase, but does not appear to induce STAT3 phosphorylation. 5TpoR induces hematopoietic myeloid differentiation in the absence of Tpo. In the presence of Tpo, the 5TpoR mutant appears to enhance erythroid differentiation when compared with the Tpo-activated wild-type TpoR. Strikingly, individual substitution of K507 or W508 to alanine also induces constitutive TpoR activation, indicating that the K and W residues within the amphipathic KWQFP motif are crucial for maintaining the unliganded receptor inactive. These residues may be targets for activating mutations in humans. Such a motif may exist in other receptors to prevent ligand-independent activation and to allow signaling via multiple flexible interfaces.
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