An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor
An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor
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DOI：
10.1182/blood-2005-06-2600
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发表时间：
2006-03-01
期刊：
影响因子：
20.3
通讯作者：
Constantinescu, SN
中科院分区：
文献类型：
--
作者：
Staerk, J;Lacout, C;Constantinescu, SN
与血小板生成素受体（TpoR）结合的配体被认为施加二聚体受体构象，导致造血干细胞更新、巨核细胞分化和血小板形成。与其他细胞因子受体（如促红细胞生成素受体）不同，TpoR在跨膜（TM）和胞质结构域之间的连接处含有两亲性KWQFP基序。我们在这里表明，突变TpoR（Δ 5TpoR），该序列被删除，是组成型活性。在没有配体的情况下，Delta 5TpoR激活Jak2、TYk2、STAT 5和促分裂原活化蛋白（MAP）激酶，但似乎不诱导STAT 3磷酸化。Δ 5TpoR在Tpo不存在的情况下诱导造血髓样分化。在Tpo的存在下，与Tpo激活的野生型TpoR相比，Delta 5TpoR突变体似乎增强了红系细胞分化。引人注目的是，K507或W508单独取代为丙氨酸也诱导组成型TpoR活化，表明两亲性KWQFP基序内的K和W残基对于维持未配体受体失活至关重要。这些残基可能是人类激活突变的靶点。这种基序可能存在于其他受体中，以防止配体非依赖性激活，并允许通过多个灵活的界面进行信号传导。
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 (Delta 5TpoR), where this sequence was deleted, is constitutively active. In the absence of ligand, Delta 5TpoR activates Jak2, TYk2, STAT5, and mitogen-activated protein (MAP) kinase, but does not appear to induce STAT3 phosphorylation. Delta 5TpoR induces hematopoietic myeloid differentiation in the absence of Tpo. In the presence of Tpo, the Delta 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.