Hofmann G, Bernabei P A, Crociani O, Cherubini A, Guasti L, Pillozzi S, Lastraioli E, Polvani S, Bartolozzi B, Solazzo V, Gragnani L, Defilippi P, Rosati B, Wanke E, Olivotto M, Arcangeli A
Department of Experimental Pathology and Oncology, University of Firenze, Viale G. B. Morgagni, 50, 50134 Florence, Italy.
J Biol Chem. 2001 Feb 16;276(7):4923-31. doi: 10.1074/jbc.M005682200. Epub 2000 Nov 15.
Integrin receptors have been demonstrated to mediate either "inside-to-out" and "outside-to-in" signals, and by this way are capable of regulating many cellular functions, such as cell growth and differentiation, cell migration, and activation. Among the various integrin-centered signaling pathways discovered so far, we demonstrated that the modulation of the electrical potential of the plasma membrane (V(REST)) is an early integrin-mediated signal, which is related to neurite emission in neuroblastoma cells. This modulation is sustained by the activation of HERG K(+) channels, encoded by the ether-à-go-go-related gene (herg). The involvement of integrin-mediated signaling is being discovered in the hemopoietic system: in particular, osteoclasts are generated as well as induced to differentiate by interaction of osteoclast progenitors with the stromal cells, through the involvement of integrin receptors. We studied the effects of cell interaction with the extracellular matrix protein fibronectin (FN) in a human leukemic preosteoclastic cell line (FLG 29.1 cells), which has been demonstrated to express HERG currents. We report here that FLG 29.1 cells indeed adhere to purified FN through integrin receptors, and that this adhesion induces an osteoclast phenotype in these cells, as evidenced by the appearance of tartrate-resistant acid phosphatase, as well as by the increased expression of CD51/alpha(v)beta(3) integrin and calcitonin receptor. An early activation of HERG current (I(HERG)), without any increase in herg RNA or modifications of HERG protein was also observed in FN-adhering cells. This activation is apparently sustained by the beta(1) integrin subunit activation, through the involvement of a pertussis-toxin sensitive G(i) protein, and appears to be a determinant signal for the up-regulation of alpha(v)beta(3) integrin, as well as for the increased expression of calcitonin receptor.
整合素受体已被证明可介导“由内向外”和“由外向内”信号，通过这种方式能够调节许多细胞功能，如细胞生长与分化、细胞迁移和激活。在迄今为止发现的各种以整合素为中心的信号通路中，我们证明质膜电位（V(REST)）的调节是一种早期整合素介导的信号，它与神经母细胞瘤细胞中的神经突发射有关。这种调节由醚 - 去极化相关基因（herg）编码的HERG钾通道的激活所维持。整合素介导的信号传导在造血系统中的作用正在被发现：特别是，破骨细胞通过破骨细胞前体与基质细胞的相互作用，经由整合素受体的参与而生成并被诱导分化。我们研究了人白血病前破骨细胞系（FLG 29.1细胞）与细胞外基质蛋白纤连蛋白（FN）相互作用的影响，该细胞系已被证明可表达HERG电流。我们在此报告，FLG 29.1细胞确实通过整合素受体粘附于纯化的FN，并且这种粘附在这些细胞中诱导了破骨细胞表型，这通过抗酒石酸酸性磷酸酶的出现以及CD51/α(v)β(3)整合素和降钙素受体表达的增加得以证明。在粘附FN的细胞中还观察到HERG电流（I(HERG)）的早期激活，而herg RNA没有任何增加或HERG蛋白没有任何修饰。这种激活显然是由β(1)整合素亚基的激活所维持，通过百日咳毒素敏感的G(i)蛋白的参与，并且似乎是α(v)β(3)整合素上调以及降钙素受体表达增加的决定性信号。
