G protein-coupled receptors desensitize and down-regulate epidermal growth factor receptors in renal mesangial cells

Area of Science:

• Cellular signaling
• Receptor biology
• Molecular pharmacology

Background:

• Plasma membrane receptors exhibit complex cross-talk.
• Epidermal growth factor receptors (EGFRs) are crucial signaling molecules.
• G protein-coupled receptors (GPCRs) are involved in diverse cellular functions.

Purpose of the Study:

• To investigate the regulation of EGFRs by endogenous GPCRs in rat renal mesangial cells.
• To elucidate the signaling pathways involved in GPCR-mediated EGFR transactivation.
• To understand the mechanisms of EGFR desensitization induced by GPCRs.

Main Methods:

• Utilized rat renal mesangial cell cultures.
• Employed various endogenous GPCRs (e.g., 5-hydroxytryptamine(2A), lysophosphatidic acid, angiotensin AT(1), bradykinin B(2)).
• Investigated signaling pathways using protein kinase C inhibitors, dominant-negative constructs, and clathrin-mediated endocytosis inhibitors.

Main Results:

• GPCRs transactivated EGFRs through a protein kinase C-dependent pathway.
• Transactivation triggered EGFR and ERK phosphorylation, and activated CREB, NF-kappaB, and E2F.
• GPCRs induced rapid EGFR down-regulation, internalization, and desensitization via clathrin-mediated endocytosis, distinct from EGF-initiated signaling.

Conclusions:

• GPCRs induce multiple cellular signals via protein kinase C-dependent EGFR transactivation.
• GPCRs mediate profound EGFR desensitization through clathrin-mediated endocytosis and loss of cell-surface receptors.
• This cross-talk mechanism highlights a novel regulatory pathway for EGFR signaling.