GPR56/ADGRG1 Activation Promotes Melanoma Cell Migration via NTF Dissociation and CTF-Mediated Gα12/13/RhoA Signaling

Chiang, Nien‐Yi; Peng, Yen-Ming; Juang, Horng‐Heng; Chen, Tse–Ching; Pan, Hsiao-Lin; Chang, Gin-Wen; Lin, Hsi‐Hsien

doi:10.1016/j.jid.2016.10.031

Cited by 36 publications

(53 citation statements)

References 58 publications

(87 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The powerful combination of ECR-targeted synthetic proteins, including monobodies and antibodies (35,40,51), with 7TM-targeted small molecule ligands will be invaluable in future mechanistic and pharmacological studies of aGPCRs.…”

Section: Discussionmentioning

confidence: 99%

Stachel -independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Salzman

Zhang

Gupta

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

View full text Add to dashboard Cite

Adhesion G protein-coupled receptors (aGPCRs) play critical roles in diverse biological processes, including neurodevelopment and cancer progression. aGPCRs are characterized by large and diverse extracellular regions (ECRs) that are autoproteolytically cleaved from their membrane-embedded signaling domains. Although ECRs regulate receptor function, it is not clear whether ECRs play a direct regulatory role in G-protein signaling or simply serve as a protective cap for the activating "Stachel" sequence. Here, we present a mechanistic analysis of ECR-mediated regulation of GPR56/ADGRG1, an aGPCR with two domains [pentraxin and laminin/neurexin/sex hormonebinding globulin-like (PLL) and G protein-coupled receptor autoproteolysis-inducing (GAIN)] in its ECR. We generated a panel of high-affinity monobodies directed to each of these domains, from which we identified activators and inhibitors of GPR56-mediated signaling. Surprisingly, these synthetic ligands modulated signaling of a GPR56 mutant defective in autoproteolysis and hence, in Stachel peptide exposure. These results provide compelling support for a ligandinduced and ECR-mediated mechanism that regulates aGPCR signaling in a transient and reversible manner, which occurs in addition to the Stachel-mediated activation.adhesion GPCR | allostery | cell signaling | monobody | protein engineering

show abstract

Section: Discussionmentioning

confidence: 99%

Stachel -independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Salzman

Zhang

Gupta

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

View full text Add to dashboard Cite

show abstract

“…Recent advances indicate that aGPCR activation is likely mediated by ligand-induced NTF displacement, followed by the unfolding and binding of an internal agonist peptide to the 7TM core of CTF (23, 24). The mechanistic insights of the “tethered agonism” of aGPCRs are increasingly being unraveled, including the coupling of unique G proteins to distinct aGPCR members (21, 25–27). However, an orderly depiction of aGPCR-mediated signaling pathways is currently lacking.…”

Section: Introductionmentioning

confidence: 99%

Activation of Adhesion GPCR EMR2/ADGRE2 Induces Macrophage Differentiation and Inflammatory Responses via Gα16/Akt/MAPK/NF-κB Signaling Pathways

Kuan-Yu

Huang

et al. 2017

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

EMR2/ADGRE2 is a human myeloid-restricted adhesion G protein-coupled receptor critically implicated in vibratory urticaria, a rare type of allergy caused by vibration-induced mast cell activation. In addition, EMR2 is also highly expressed by monocyte/macrophages and has been linked to neutrophil migration and activation. Despite these findings, little is known of EMR2-mediated signaling and its role in myeloid biology. In this report, we show that activation of EMR2 via a receptor-specific monoclonal antibody promotes the differentiation of human THP-1 monocytic cell line and induces the expression of pro-inflammatory mediators, including IL-8, TNF-α, and MMP-9. Using specific signaling inhibitors and siRNA knockdowns, biochemical and functional analyses reveal that the EMR2-mediated signaling is initiated by Gα16, followed by the subsequent activation of Akt, extracellular signal-regulated kinase, c-Jun N-terminal kinase, and nuclear factor kappa-light-chain-enhancer of activated B cells. Our results demonstrate a functional role for EMR2 in the differentiation and inflammatory activation of human monocytic cells and provide potential targets for myeloid cell-mediated inflammatory disorders.

show abstract

“…Interestingly, Adgrg1 has been related to angiogenesis [22] and RACK1 overexpressing melanomas did appear to contain more αSMA + cells, a marker of angiogenesis. Adgrg1 activation was recently shown to promote melanoma migration [37]. Melanomas have a high angiogenic potential.…”

Section: Discussionmentioning

confidence: 99%

RACK1 cooperates with NRAS to promote melanoma in vivo

Campagne

Reyes-Gomez

Picco

et al. 2017

Cellular Signalling

View full text Add to dashboard Cite

Melanoma is the deadliest skin cancer. RACK1 (Receptor for activated protein kinase C) protein was proposed as a biological marker of melanoma in human and domestic animal species harboring spontaneous melanomas. As a scaffold protein, RACK1 is able to coordinate the interaction of key signaling molecules implicated in both physiological cellular functions and tumorigenesis. A role for RACK1 in rewiring ERK and JNK signaling pathways in melanoma cell lines had been proposed. Here, we used a genetic approach to test this hypothesis in vivo in the mouse. We show that Rack1 knock-down in the mouse melanoma cell line B16 reduces invasiveness and induces cell differentiation. We have developed the first mouse model for RACK1 gain of function, Tyr::Rack1-HA transgenic mice, targeting RACK1 to melanocytes in vivo. RACK1 overexpression was not sufficient to initiate melanomas despite activated ERK and AKT. However, in a context of melanoma predisposition, RACK1 overexpression reduced latency and increased incidence and metastatic rate. In primary melanoma cells from Tyr::Rack1-HA, Tyr::NRas mice, activated JNK (c-Jun N-terminal kinase) and activated STAT3 (signal transducer and activator of transcription 3) acted as RACK1 oncogenic partners in tumoral progression. A sequential and coordinated activation of ERK, JNK and STAT3 with RACK1 is shown to accelerate aggressive melanoma development in vivo.

show abstract

GPR56/ADGRG1 Activation Promotes Melanoma Cell Migration via NTF Dissociation and CTF-Mediated Gα12/13/RhoA Signaling

Cited by 36 publications

References 58 publications

Stachel -independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Stachel -independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Activation of Adhesion GPCR EMR2/ADGRE2 Induces Macrophage Differentiation and Inflammatory Responses via Gα16/Akt/MAPK/NF-κB Signaling Pathways

RACK1 cooperates with NRAS to promote melanoma in vivo

Contact Info

Product

Resources

About