A Hematopoietic Perspective on the Promiscuity and Specificity of Gα₁₆ Signaling

Abstract

Gα₁₆, a member of G_q subfamily, is expressed exclusively in hematopoietic cells, and its expression is highly modulated during lineage differentiation. Although functional redundancy within G_q subclass members has been observed in many established models, Gα₁₆possesses unique structural and biochemical properties not shared by other family members. Its broad receptor-coupling capacity and unique downstream binding partners and effectors allow the occurrence of both inositol lipid-dependent and -independent signals. Apart from its recognized biological functions in hematopoietic cell responses, the enlistment of complicated signaling pathways further signifies the importance of Gα₁₆in signal integration. This review aims to provide an updated appreciation and rational discussion of Gα₁₆ signaling with regard to its promiscuity and specificity.

The puzzling uniqueness of the heterotrimeric G15 protein and its potential beyond hematopoiesis

“…A steady interaction of wild-type P2Y2 receptor with Ga15 was assessed by FRET even in the absence of ligand (Kotevic et al 2005). The presence of G15 biased the pharmacological profile of the k opioid receptor (Su et al 2009), again suggesting the existence of preformed receptor-G protein complexes. A similar interaction with G15 may even interfere with the activation of other G protein subtypes as shown for pUS28 (Moepps et al 2008), a viral GPCR characterized by elevated ligand-independent constitutive activity and by increased phosphorylation (Minisini et al 2003).…”

“…Consequently, a wealth of attention was focused on early maturation stages of hematopoiesis (Hubbard & Hepler 2006, Su et al 2009) such as cluster of differentiation 34 (CD34) positive hematopoietic stem cells (HSCs; Tenailleau et al 1997, Pfeilstocker et al 2000, erythroid precursors (Ghose et al 1999), megakaryocytic (den Dekker et al 2001a,b), and B cells progenitors (Mapara et al 1995). The expression of Ga15 is subsequently lost upon cell maturation.…”

“…Despite broadly described as hematopoietic specific (Amatruda et al 1991, Hubbard & Hepler 2006, Su et al 2009), G15 expression was occasionally reported in tissues that are not part of the immune system, particularly in a variety of epithelia. While analyzing baboon skin by in situ hybridization, Rock et al (1997) reported the presence of Ga15 in hair follicular epithelium.…”

CCR1-Mediated STAT3 Tyrosine Phosphorylation and CXCL8 Expression in THP-1 Macrophage-like Cells Involve Pertussis Toxin-Insensitive Gα14/16 Signaling and IL-6 Release

“…c-Fos expression and transcriptional activation is induced upon Ga 16 activation (19), and constitutively active mutants of Ga 14 and Ga 16 were demonstrated to enhance the activity of STAT3 in cotransfection systems (20,21). The coexistence of Ga 14/16 and CCR1, as well as their demonstrated functional coupling in THP-1 macrophage-like cells (2,(22)(23)(24)(25)(26), suggests that CCR1 may use Ga 14/16 to stimulate STAT3. There is increasing evidence to support a role for STAT3 activation in CCR1-mediated cellular responses.…”

G protein signaling controls the differentiation of multiple cell lineages

“…well-summarized in other reviews and are beyond the scope of this article [6]. In addition to their function in regulating mature blood system, GPCRs mediate the development of blood cells by regulating their proliferation and differentiation [32]. A recently identified orphan GPCR, Gpr48/LGR4 appeared to be required for definitive erythropoiesis in mice.…”