The Hedgehog (Hh) family of secreted signaling proteins plays important roles in organogenesis and patterning of the embryo. Loss of the Hh signaling results in severe developmental defects, whereas aberrant activation of the Hh pathway is associated with several common types of human cancer. A thorough understanding of the molecular mechanism of Hh signal transduction is crucial for prevention and remedy of the abnormalities related to the Hh pathway. In mice, Hh signaling is primarily mediated by the Gli2 and Gli3 transcription factors. Gli2 is generally considered to be a transcriptional activator, while Gli3 acts largely as a repressor, though it also has a weak activator function. The distinct functions of Gli2 and Gli3 is primarily attributed to their intrinsic molecular properties, and is also due to the fact that in the absence of Hh signaling, the majority of the full-length Gli3 protein undergoes the proteasome-mediated processing to a C-terminally truncated repressor, while only a small fraction of Gli2 is processed. The processing of both proteins is induced by the phosphorylation of the first four of the six protein kinase A (PKA) sites at their C-termini. Hh signaling inhibits Gli2 and Gli3 processing and generates the full-length Gli2 and Gli3 proteins. However, full- length Gli2 itself is not sufficient to activate Hh target genes and thus has to be converted into an activator;this conversion is also dependent on Hh signaling. To date, the mechanism of production and molecular nature of the Gli2 activator are unknown. Our preliminary studies indicate that post-translational modification plays a critical role in the regulation of Gli2 transcriptional activity. We thus hypothesize that Hh signaling activates full-length Gli2 protein by regulating its post-translational modification. We will test this hypothesis by perusing two specific aims.
Aim 1. To understand the biological significance and mechanism of PKA phosphorylation- mediated suppression of Gli2 activity;
Aim 2. To understand the role of SUMO modification in the regulation of Gli2 activity and the molecular mechanism underlying it. The completion of the proposed study will significantly advance our understanding of the molecular mechanisms by which Hh signaling regulates Gli2 transcriptional activity. It may also give us insight into the molecular mechanisms of the human birth defects and cancer associated with abnormal Hh signaling.
The Hedgehog (Hh) family of secreted signaling proteins plays fundamental roles in cell fate specification and cell proliferation and differentiation. Loss of Hh signaling results in a wide range of birth defects, whereas aberrant activation of the Hh pathway causes several types of human cancer. Understanding the molecular mechanism of Hh signaling may provide insights into the design of therapeutic agents to modulate Hh pathway activity and therefore prevent or treat birth defects and cancers caused by misregulation of the Hh signaling activity.
|Wu, Chuanqing; Yang, Mei; Li, Juan et al. (2014) Talpid3-binding centrosomal protein Cep120 is required for centriole duplication and proliferation of cerebellar granule neuron progenitors. PLoS One 9:e107943|
|Wang, Chengbing; Low, Wee-Chuang; Liu, Aimin et al. (2013) Centrosomal protein DZIP1 regulates Hedgehog signaling by promoting cytoplasmic retention of transcription factor GLI3 and affecting ciliogenesis. J Biol Chem 288:29518-29|
|Han, Lizhang; Pan, Yong; Wang, Baolin (2012) Small ubiquitin-like Modifier (SUMO) modification inhibits GLI2 protein transcriptional activity in vitro and in vivo. J Biol Chem 287:20483-9|
|Li, Juan; Wang, Chengbing; Pan, Yong et al. (2011) Increased proteolytic processing of full-length Gli2 transcription factor reduces the hedgehog pathway activity in vivo. Dev Dyn 240:766-74|
|Cui, Cheng; Chatterjee, Bishwanath; Francis, Deanne et al. (2011) Disruption of Mks1 localization to the mother centriole causes cilia defects and developmental malformations in Meckel-Gruber syndrome. Dis Model Mech 4:43-56|
|Wang, Chengbing; Pan, Yong; Wang, Baolin (2010) Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors. Development 137:2001-9|
|Pan, Yong; Wang, Chengbing; Wang, Baolin (2009) Phosphorylation of Gli2 by protein kinase A is required for Gli2 processing and degradation and the Sonic Hedgehog-regulated mouse development. Dev Biol 326:177-89|
|Low, Wee-Chuang; Wang, Chengbing; Pan, Yong et al. (2008) The decoupling of Smoothened from Galphai proteins has little effect on Gli3 protein processing and Hedgehog-regulated chick neural tube patterning. Dev Biol 321:188-96|
|Pan, Yong; Wang, Baolin (2007) A novel protein-processing domain in Gli2 and Gli3 differentially blocks complete protein degradation by the proteasome. J Biol Chem 282:10846-52|
|Pan, Yong; Bai, Chunyang Brian; Joyner, Alexandra L et al. (2006) Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol 26:3365-77|