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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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Submitted July 5, 2005
Accepted October 15, 2005
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*
Ludwig Institute for Cancer Research, Bruxelles, Belgium; Christian de Duve Institute of Cellular Pathology & MEXP Unit, Universite de Louvain, Brussels, Belgium
INSERM U362, Institute Gustave Roussy, Villejuif Cedex, France
Center for Structural Biology, Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA
* Corresponding author; email: stefan.constantinescu{at}bru.licr.org.
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 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 to 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 un-liganded 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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