Signaling mechanisms and physiological functions of G‐protein Gα₁₃ in blood vessel formation, bone homeostasis, and cancer

Abstract

Heterotrimeric G-proteins are cellular signal transducers. They mainly relay signals from G-protein-coupled receptors (GPCRs). GPCRs function as guanine nucleotide-exchange factors to active these G-proteins. Based on the sequence and functional similarities, these G-proteins are grouped into four subfamilies: G s , G i , G q , and G 12/13 . The G 12/13 subfamily consists of two members: G 12 and G 13 . G 12/13 -mediated signaling pathways play pivotal roles in a variety of physiological processes, while aberrant regulation of this pathway has been identified in various human diseases. Here we summarize the signaling mechanisms and physiological functions of Gα 13 in blood vessel formation and bone homeostasis. We further discuss the expanding roles of Gα 13 in cancers, serving as oncogenes as well as tumor suppressors.

Gα13 loss promotes tumor progression in the KPC transgenic mouse model of advanced pancreatic cancer

“…Since GPCRs can signal through the G12 family of small G proteins (Kurose, 2003), many studies have evaluated the contribution of Gα12 and Gα13 to physiologic and pathologic processes (Sriram et al, 2020;Syrovatkina and Huang, 2019;Tutunea-Fatan et al, 2020).…”

“…There is increasing interest in understanding the role of effectors downstream of GPCRs and determining whether these effectors could be potential therapeutic targets (Hauser et al, 2017). Since GPCRs can signal through the G12 family of small G proteins (Kurose, 2003), many studies have evaluated the contribution of Gα12 and Gα13 to physiologic and pathologic processes (Sriram et al, 2020; Syrovatkina and Huang, 2019; Tutunea-Fatan et al, 2020). These studies, which have been primarily performed in epithelial cancer cell lines, showed that Gα13 functions as a tumor promoter (Chow et al, 2016; Kelly et al, 2007; Kelly et al, 2006; Kozasa et al, 2011; Rasheed et al, 2018; Zhang et al, 2018).…”

Allosteric Modulator Leads Hiding in Plain Site: Developing Peptide and Peptidomimetics as GPCR Allosteric Modulators

“…orthosteric agonist affinity via "positive cooperativity." Receptor contacts with transducer proteins (e.g., Gα (Dutka et al, 2019;Syrovatkina and Huang, 2019), β-arrestin (Shukla et al, 2013))-and accessory proteins (e.g., receptor complement proteins (RCPs) (Routledge et al, 2020), receptor activity modulating proteins (RAMPs) (J Gingell et al, 2016), GPCR oligomers (Borroto-Escuela et al, 2013;Pin et al, 2019), receptor tyrosine kinases (RTKs) (Di Liberto et al, 2019), the protein phosphatase and tensin homolog (PTEN) (Anastasio et al, 2013), and others (Pasternak, 2017))-allosterically regulate receptor function. Therefore, these endogenous protein AMs can provide valuable lead peptide AM sequences, often with available structural, biochemical, and computational information to guide lead development/optimization (Figure 2).…”

The emerging roles of Gα12/13 proteins on the hallmarks of cancer in solid tumors

“…Tumor cells cleverly hijack these physiological mechanisms to induce tumor angiogenesis, and this process is important not only for survival of tumor cells but also for their ability to metastasize to distant organs [ 64 ]. A role for Gα13 in angiogenesis was revealed from knockout of both copies of the gene in mice, where embryonic lethality was found to be due to lack of blood vessel formation [ 11 , 65 ].…”