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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.Received 19 June 2003; received after revision 10 July 2003; accepted 21 July 2003 相似文献
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X. H. Bai D. W. Wang Y. Luan X. P. Yu C. J. Liu 《Cellular and molecular life sciences : CMLS》2009,66(4):667-680
ADAMTS-12, a metalloproteinase that belongs to ADAMTS family, is strongly upregulated during chondrogenesis and demonstrates
prominent expression in the growth plate chondrocytes. ADAMTS-12 potently inhibits chondrocyte differentiation, as revealed
by altered expression of both early and later genes critical for chondrogenesis. In addition, ADAMTS-12-mediated inhibition
of chondrogenesis depends on its enzymatic activity, since its point mutant lacking enzymatic activity completely loses this
activity. Furthermore, the C-terminal four thrombospondin motifs known to bind COMP substrate is necessary for its full proteolytic
activity and inhibition of chondrocyte differentiation. Mechanism studies demonstrate that ADAMTS-12 induces PTHrP, whereas
it inhibits IHH during chondrogenesis. Furthermore, PTHrP induces ADAMTS-12 and ADAMTS-12 is hardly detectable in PTHrP-/-growth
plate chondrocytes. Importantly, knocking down ADAMTS-12 mRNA levels or blocking ADAMTS-12 activity almost abolishes the PTHrP-mediated
inhibition of type X collagen expression. Collectively, these findings demonstrate that ADAMTS-12, a downstream molecule of
PTHrP signaling, is a novel regulator of chondrogenesis.
X. H. Bai, D.W. Wang: These two authors contributed equally to this work. 相似文献
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ERKs are the point of divergence of PKA and PKC activation by PTHrP in human skin fibroblasts 总被引:3,自引:0,他引:3
Fortino V Torricelli C Gardi C Valacchi G Rossi Paccani S Maioli E 《Cellular and molecular life sciences : CMLS》2002,59(12):2165-2171
Parathyroid hormone-related peptide (PTHrP) receptors, coupled to trimeric G proteins, operate in most target cells through
at least three different transduction routes: Gαs-mediated stimulation of adenylylcyclase (AC), Gαq-mediated activation of
phospholipase Cβ (PLC) and mitogen-activated protein kinase (MAPK) activation. In this study we investigated the relative
role of different pathways in human skin fibroblast prolifera-tion. Using chemical inhibitors and activators of signal transduction,
we demonstrated that: (i) AC/cAMP and PLC/1,4,5 inositol triphosphate/diacylglycerol second-messenger systems are simultaneously
activated following PTHrP binding to its receptors; (ii) the mitogenic response to PTHrP derives from a balance between two
counteracting pathways – an activating route mediated by protein kinase C (PKC) and an inhibitory route mediated by protein
kinase A (PKA); (iii) PTHrP mitogenic effects are largely dependent on MAPKs, whose activity can be modulate
d by both PKA and PKC. Our results indicate that MAPKs are common targets of both transduction routes and, at the same time,
their point of divergence in mediating PTHrP dual and opposite mitogenic effects.
Received 2 August 2002; received after revision 10 September 2002; accepted 18 October 2002
RID="*"
ID="*"Corresponding author. 相似文献
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