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Adhesion GPCR Latrophilin-2 Specifies Cardiac Lineage Commitment through CDK5, Src, and P38MAPK.

ABSTRACT: Identifying lineage-specific markers is pivotal for understanding developmental processes and developing cell therapies. Here, we investigated the functioning of a cardiomyogenic cell-surface marker, latrophilin-2 (LPHN2), an adhesion G-protein-coupled receptor, in cardiac differentiation. LPHN2 was selectively expressed in cardiac progenitor cells (CPCs) and cardiomyocytes (CMCs) during mouse and human pluripotent stem cell (PSC) differentiation; cell sorting with an anti-LPHN2 antibody promoted the isolation of populations highly enriched in CPCs and CMCs. Lphn2 knockdown or knockout PSCs did not express cardiac genes. We used the Phospho Explorer Antibody Array, which encompasses nearly all known signaling pathways, to assess molecular mechanisms underlying LPHN2-induced cardiac differentiation. LPHN2-dependent phosphorylation was the strongest for cyclin-dependent kinase 5 (CDK5) at Tyr15. We identified CDK5, Src, and P38MAPK as key downstream molecules of LPHN2 signaling. These findings provide a valuable strategy for isolating CPCs and CMCs from PSCs and insights into the still-unknown cardiac differentiation mechanisms.

SUBMITTER: Lee CS

PROVIDER: S-EPMC8072181 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Adhesion GPCR, latrophilin-2, specifies cardiac lineage commitment through CDK5, Src, and P38MAPK

Project description:Identifying lineage-specific markers is pivotal for understanding developmental processes and developing cell therapies. Here, we report a new cardiomyogenic cell surface marker latrophilin-2 (Lphn2), an adhesion G protein-coupled receptor. When mouse and human pluripotent stem cells (PSCs) were stimulated with BMP4, Activin A, and bFGF, they differentiated into cardiac lineage cells. Lphn2 was selectively expressed on cardiac progenitor cells (CPCs) and cardiomyocytes (CMCs) during the differentiation of mouse PSCs, and cell sorting with an anti-Lphn2 antibody promoted the isolation of populations highly enriched in CPCs and CMCs. Lphn2 knock-down or knock-out PSCs did not express cardiac genes. To investigate the molecular mechanism underlying the induction of cardiac differentiation by Lphn2, we used the Phospho Explorer Antibody Array, which encompasses nearly all known signaling pathways. Lphn2-dependent phosphorylation was strongest for cyclin-dependent kinase 5 (CDK5) at Tyr15. We identified CDK5, Src, and P38MAPK as key downstream molecules of Lphn2. These findings provide a valuable tool for isolating cardiomyogenic progenitors and CMCs from PSCs and shed light on the still-unknown mechanisms of cardiac differentiation.

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Data for Alternative Splicing of Adhesion-GPCR Latrophilin-3 Controls Synapse Formation

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