Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types
Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types
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DOI：
10.1074/jbc.m205749200
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发表时间：
2002-09-27
影响因子：
4.8
通讯作者：
Wellstein, A
中科院分区：
文献类型：
--
作者：
Stoica, GE;Kuo, A;Wellstein, A
中期因子（MK）是一种发育调节的分泌型生长因子，与多效生长因子（PTN）同源。为了研究MK在肿瘤生长中的潜在作用，我们在人SW-13细胞中表达MK，并研究MK的受体结合、信号转导和活性。MK蛋白在低ng/ml范围内刺激体外软琼脂集落形成和SW-13细胞在无胸腺裸鼠中的肿瘤生长，以及来自脑微血管系统和脐静脉（HUVEC）的人内皮细胞的增殖。MK与间变性淋巴瘤激酶（ALK）结合，即PTN的受体，在完整细胞中的表观Kd为170 pM，MK与该受体的结合被PTN竞争，表观Kd接近20 pM。针对ALK胞外配体结合结构域的单克隆抗体可抑制MK的ALK受体结合以及MK刺激的SW-13细胞集落形成。此外，MK刺激WI-38人成纤维细胞中的ALK磷酸化，并激活表达ALK蛋白的WI-38、HLTVEC、神经母细胞瘤（SH SY-5 Y）和胶质母细胞瘤（U87 MG）细胞中的PI 3-激酶和MAP激酶信号转导。我们的结论是MK可以作为一种生长，生存和血管生成因子在肿瘤发生和信号通过ALK受体。
Midkine (MK) is a developmentally regulated, secreted growth factor homologous to pleiotrophin (PTN). To investigate the potential role of MK in tumor growth, we expressed MK in human SW-13 cells and studied receptor binding, signal transduction, and activity of MK. The MK protein stimulates soft agar colony formation in vitro and tumor growth of SW-13 cells in athymic nude mice, as well as proliferation of human endothelial cells from brain microvasculature and umbilical vein (HUVEC) in the low ng/ml range. MK binds to anaplastic lymphoma kinase (ALK), the receptor for PTN, with an apparent K-d of 170 pm in intact cells, and this receptor binding of MK is competed by PTN with an apparent Kd of similar to20 pM. Monoclonal antibodies raised against the extracellular ligand-binding domain of ALK inhibit ALK receptor binding of MK as well as MK-stimulated colony formation of SW-13 cells. Furthermore, MK stimulates ALK phosphorylation in WI-38 human fibroblasts and activates PI3-kinase and MAP kinase signal transduction in WI-38, HLTVEC, neuroblastoma (SH SY-5Y) an glioblastoma (U87MG) cells that express the ALK protein. We conclude that MK can act as a growth, survival, and angiogenic factor during tumorigenesis and signals through the ALK receptor.