Maioli E, Fortino V
Department of Physiology, University of Siena, Via Aldo Moro, 8, 53100 Siena, Italy.
Cell Mol Life Sci. 2004 Feb;61(3):257-62. doi: 10.1007/s00018-003-3233-2.
Our understanding of the mode of action of parathyroid hormone-related protein (PTHrP) has changed profoundly during the last decade. Most PTHrP activities are mediated by membrane receptors through autocrine/paracrine pathways. However, both endogenous and exogenous PTHrP also appear to have intracrine effects through translocation into the nucleus. The present review proposes unconventional PTHrP signalling, based on novel clues. First, PTHrP binding to its membrane receptor triggers internalization of the whole complex, mediated by beta-arrestin. There is growing evidence that the receptor and arrestin are the effectors of biological responses, rather than the ligand (or in addition to the ligand). Second, the existence of putative PTHrP targets within the cytoplasm is beginning to be supported. Recent findings of interactions between a COOH-terminus of PTHrP and beta-arrestin and between the PTHrP receptor and 14-3-3 proteins represent the starting point for identification of intracellular partners of both the hormone and its receptor.
在过去十年中，我们对甲状旁腺激素相关蛋白（PTHrP）作用模式的理解发生了深刻变化。大多数PTHrP活性是通过自分泌/旁分泌途径由膜受体介导的。然而，内源性和外源性PTHrP似乎也通过转位进入细胞核而产生胞内作用。本综述基于新线索提出了非传统的PTHrP信号传导。首先，PTHrP与其膜受体结合会触发整个复合物的内化，这是由β-抑制蛋白介导的。越来越多的证据表明，受体和抑制蛋白是生物学反应的效应器，而不是配体（或者除了配体之外）。其次，细胞质中假定的PTHrP靶点的存在开始得到支持。PTHrP的COOH末端与β-抑制蛋白之间以及PTHrP受体与14-3-3蛋白之间相互作用的最新发现，是鉴定该激素及其受体细胞内伙伴的起点。
