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The heterogeneous response of acute myeloid leukemia (AML) to current anti‐leukemic therapies is only partially explained by mutational heterogeneity. We previously identified GPR56 as a surface marker associated with poor outcome across genetic groups, which characterizes two leukemia stem cell (LSC)‐enriched compartments with different self‐renewal capacities. How these compartments self‐renew remained unclear. Here, we show that GPR56+ LSC compartments are promoted in a complex network involving epithelial‐to‐mesenchymal transition (EMT) regulators besides Rho, Wnt, and Hedgehog (Hh) signaling. Unexpectedly, Wnt pathway inhibition increased the more immature, slowly cycling GPR56+CD34+ fraction and Hh/EMT gene expression, while Wnt activation caused opposite effects. Our data suggest that the crucial role of GPR56 lies in its ability to co‐activate these opposing signals, thus ensuring the constant supply of both LSC subsets. We show that CDK7 inhibitors suppress both LSC‐enriched subsets in vivo and synergize with the Bcl‐2 inhibitor venetoclax. Our data establish reciprocal transition between LSC compartments as a novel concept underlying the poor outcome in GPR56high AML and propose combined CDK7 and Bcl‐2 inhibition as LSC‐directed therapy in this disease. Synopsis: RNA‐ and ATAC‐seq profiling combined with functional in vitro and in vivo studies unravel the multi‐faceted roles of GPR56, a surface marker associated with high leukemia stem cell (LSC) burden and poor prognosis in acute myeloid leukemia (AML). ATAC‐seq profiling of 35 primary AML specimens links high GPR56 expression to Wnt and Hh signaling.GPR56 is required for in vitro and in vivo expansion of primary human AML cells.GPR56 enhances besides RhoA also TGFB, Hedgehog, and Wnt pathway activities, which inhibit each other to coordinate reciprocal transition between the GPR56+CD34+ and GPR56+CD34− compartments to sustain the LSC pool.CDK7 inhibitors synergize with the Bcl‐2 inhibitor venetoclax to suppress both GPR56+ LSC‐enriched compartments in vitro and in vivo. [ABSTRACT FROM AUTHOR]

The adhesion class of G protein-coupled receptors (GPCRs) is the second largest family of GPCRs (33 members in humans). Adhesion GPCRs (aGPCRs) are defined by a large extracellular N-terminal region that is linked to a C-terminal seven transmembrane (7TM) domain via aGPCR-autoproteolysis inducing (GAIN) domain containing a GPCR proteolytic site (GPS).Most aGPCRs undergo autoproteolysis at the GPS motif, but the cleaved fragments stay closely associated, with the N-terminal fragment (NTF) bound to the 7TMof the C-terminal fragment (CTF). The NTFs ofmost aGPCRs contain domains known to be involved in cell-cell adhesion, while the CTFs are involved in classical G protein signaling, as well as other intracellular signaling. In this workshop report, we review themost recent findings on the biology, signaling mechanisms, and physiological functions of aGPCRs. [ABSTRACT FROM AUTHOR]

The class of adhesion G protein-coupled receptors (aGPCRs), with 33 human homologs, is the second largest family of GPCRs. In addition to a seven-transmembrane α-helix-a structural feature of all GPCRs-the class of aGPCRs is characterized by the presence of a large N-terminal extracellular region. In addition, all aGPCRs but one (GPR123) contain a GPCR autoproteolysis-inducing (GAIN) domain that mediates autoproteolytic cleavage at the GPCR autoproteolysis site motif to generate N- and a C-terminal fragments (NTF and CTF, respectively) during protein maturation. Subsequently, the NTF and CTF are associated noncovalently as a heterodimer at the plasma membrane. While the biological function of the GAIN domain-mediated autocleavage is not fully understood, mounting evidence suggests that the NTF and CTF possess distinct biological activities in addition to their function as a receptor unit. We discuss recent advances in understanding the biological functions, signaling mechanisms, and disease associations of the aGPCRs. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) comprise an expanded superfamily of receptors in the human genome. Adhesion class G protein-coupled receptors (adhesion-GPCRs) form the second largest class of GPCRs. Despite the abundance, size, molecular structure, and functions in facilitating cell and matrix contacts in a variety of organ systems, adhesion-GPCRs are by far the most poorly understood GPCR class. Adhesion-GPCRs possess a unique molecular structure, with extended N-termini containing various adhesion domains. In addition, many adhesion-GPCRs are autoproteolytically cleaved into an N-terminal fragment (NTF, NT, α-subunit) and C-terminal fragment (CTF, CT, β-subunit) at a conserved GPCR autoproteolysis-inducing (GAIN) domain that contains a GPCR proteolysis site (GPS). These two features distinguish adhesion-GPCRs from other GPCR classes. Though active research on adhesion-GPCRs in diverse areas, such as immunity, neuroscience, and development and tumor biology has been intensified in the recent years, the general biological and pharmacological properties of adhesion-GPCRs are not well known, and they have not yet been used for biomedical purposes. The '6th International Adhesion-GPCR Workshop,' held at the Institute of Physiology of the University of Würzburg on September 6-8, 2012, assembled a majority of the investigators currently actively pursuing research on adhesion-GPCRs, including scientists from laboratories in Europe, the United States, and Asia. The meeting featured the nascent mechanistic understanding of the molecular events driving the signal transduction of adhesion-GPCRs, novel models to evaluate their functions, and evidence for their involvement in human disease. [ABSTRACT FROM AUTHOR]

Background The 2-chloro-N6-cyclopentyladenosine (CCPA) was proven to be a protective factor in ischemic reperfusion injury in myocardium and to reduce the infarct size in the heart. The purpose of this study was to determine whether flap necrosis could be reduced by intravenous administration of CCPA. Methods Fifty-six male Wistar rats were divided into 4 experimental groups. An epigastric adipocutaneous flap was raised, and the area of flap necrosis was assessed for all groups on the fifth postoperative day with planimetry software. Results The control group had a significantly lower rate of flap necrosis than the ischemic control group ( p < .05). The nonischemic CCPA group had a significantly lower rate of flap necrosis than the nonischemic control group ( p < .05). The ischemic CCPA group had a highly significant ( p < .0001) rate of lower flap necrosis than the ischemic control group. Conclusion Our data show that reduction of flap necrosis can be achieved both with and without ischemic periods by intravenous administration of CCPA. © 2011 Wiley Periodicals, Inc. Head Neck, 2011 [ABSTRACT FROM AUTHOR]