Maier Dominic, Cheng Shuofei, Hipfner David R
Institut de recherches cliniques de Montréal; Montreal, QC Canada.
Fly (Austin). 2012 Jul-Sep;6(3):135-41. doi: 10.4161/fly.20245. Epub 2012 Jun 1.
Hedgehog (Hh) signaling is essential for proper tissue patterning and maintenance and has a substantial impact on human disease. While many of the main components and mechanisms involved in transduction of the Hh signal have been identified, the details of how the pathway functions are continually being refined. One aspect that has attracted much attention recently is the involvement of G-protein-coupled receptor kinases (GRKs) in the pathway. These regulators of G-protein-coupled receptor (GPCR) signaling have an evolutionarily-conserved function in promoting high-threshold Hh target gene expression through regulation of Smoothened (Smo), a GPCR family member that activates intracellular Hh signaling. Several models of how GRKs impact on Smo to increase downstream signaling have been proposed. Recently, we demonstrated that these kinases have surprisingly complex and conflicting roles, acting to limit signaling through the pathway while also promoting Smo activity. In addition to the previously described direct effects of Gprk2 on Smo activation, Gprk2 also indirectly affects Hh signaling by controlling production of the second messenger cyclic AMP to influence Protein kinase A activity.
刺猬信号通路（Hh）对于组织的正常模式形成和维持至关重要，并且对人类疾病有重大影响。虽然已经确定了许多参与Hh信号转导的主要成分和机制，但该通路的具体功能细节仍在不断完善。最近备受关注的一个方面是G蛋白偶联受体激酶（GRKs）参与该通路。这些G蛋白偶联受体（GPCR）信号的调节因子在通过调节Smoothened（Smo）来促进高阈值Hh靶基因表达方面具有进化保守功能，Smo是一种激活细胞内Hh信号的GPCR家族成员。已经提出了几种GRKs如何影响Smo以增加下游信号传导的模型。最近，我们证明这些激酶具有惊人的复杂和矛盾的作用，既通过该通路限制信号传导，同时又促进Smo活性。除了先前描述的Gprk2对Smo激活的直接作用外，Gprk2还通过控制第二信使环磷酸腺苷的产生来间接影响Hh信号传导，从而影响蛋白激酶A的活性。
