Insulin-like growth factor-binding protein-5 (IGFBP-5) stimulates growth and IGF-I secretion in human intestinal smooth muscle by Ras-dependent activation of p38 MAP kinase and Erk1/2 pathways
Insulin-like growth factor-binding protein-5 (IGFBP-5) stimulates growth and IGF-I secretion in human intestinal smooth muscle by Ras-dependent activation of p38 MAP kinase and Erk1/2 pathways
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DOI：
10.1074/jbc.m200885200
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发表时间：
2002-06-07
影响因子：
4.8
通讯作者：
Zhou, HP
中科院分区：
文献类型：
--
作者：
Kuemmerle, JF;Zhou, HP
胰岛素样生长因子结合蛋白-5（IGFBP-5）和胰岛素样生长因子-I（IGF-I）由人肠平滑肌细胞产生。内源性IGF-I刺激生长并增加IGFBP-5分泌。IGFBP-5通过促进IGF-I与IGF-I受体酪氨酸激酶的相互作用增强IGF-I的作用。Andress（Andress，D. L.（1998）Aim J.Physiol.274，E744-E750）和Berfield等人（Berfield，A. K.，Andress，D. L.，和Abrass，C. K.（2000）Kidney Int.57，1991-2003）已经表明，在成骨细胞和肾系膜细胞中，IGFBP-5刺激增殖和丝状伪足形成，而不依赖于IGF-I，推测是通过激活不同的IGFBP-5受体丝氨酸激酶。本研究确定了IGFBP-5是否对人肠平滑肌细胞的生长产生直接影响，并确定了所涉及的细胞内信号通路。IGFBP-5引起[H-3]胸苷掺入的浓度依赖性增加和IGF-I分泌的增加，其发生独立于IGF-I和IGF-I受体酪氨酸激酶。IGFBP-5诱导的p38阿拉普激酶磷酸化（可被SB 203580消除）或显性失活Pas突变体Ras（S17 N）表达，以及Erk 1/2磷酸化（可被Raf 1激酶抑制剂U1026消除）或Ras（S17 N）表达。SB 203580或U1026可部分抑制IGFBP-5刺激的[H-3]胸苷掺入和IGF-I分泌，并通过两种抑制剂的组合或Ras（S17 N）的表达而消除。这些数据表明，IGFBP-5通过激活p38 MAP激酶依赖性和Erk 1/2依赖性途径刺激人肠平滑肌细胞的生长和IGF-I分泌，这些途径不依赖于IGF-I。因此，正反馈机制将IGFBP-5和IGF-I分泌联系起来，加强了它们对生长的个体影响。
Insulin-like growth factor-binding protein-5 (IGFBP-5) and insulin-like growth factor-I (IGF-I) are produced by human intestinal smooth muscle cells. Endogenous IGF-I stimulates growth and increases IGFBP-5 secretion. IGFBP-5 augments the effects of IGF-I by facilitating interaction of IGF-I with the IGF-I receptor tyrosine kinase. Andress (Andress, D. L. (1998) Aim J. Physiol. 274, E744-E750) and Berfield et al. (Berfield, A. K., Andress, D. L., and Abrass, C. K. (2000) Kidney Int. 57, 1991-2003) have shown that in osteoblasts and kidney mesangial cells, IGFBP-5 stimulates proliferation and filopodia formation independently of IGF-I, presumably by activating a distinct IGFBP-5 receptor serine kinase. The present study determined whether IGFBP-5 exerts direct effects on growth in human intestinal smooth muscle cells and identified the intracellular signaling pathways involved. IGFBP-5 caused a concentration-dependent increase in [H-3]thymidine incorporation and an increase in IGF-I secretion that occurred independently of IGF-I and the IGF-I receptor tyrosine kinase. IGFBP-5-induced phosphorylation of p38 ALAP kinase, which was abolished by SB203580, or expression of a dominant negative Pas mutant, Ras(S17N), and phosphorylation of Erk1/2, which was abolished by a Raf1 kinase inhibitor, U1026, or expression of Ras(S17N). IGFBP-5-stimulated [H-3]thymidine incorporation and IGF-I secretion were partly inhibited by SB203580 or U1026 and abolished by the combination of the two inhibitors or by expression of Ras(S17N). These data show that IGFBP-5 stimulates growth and IGF-I secretion in human intestinal smooth muscle cells by activation of p38 MAP kinase-dependent and Erk1/2-dependent pathways that are independent of IGF-I. A positive feedback mechanism therefore links IGFBP-5 and IGF-I secretion that reinforces their individual effects on growth.