Sharpening the edges of understanding the structure/function of the LPA1 receptor: Expression in cancer and mechanisms of regulation

Mandi M. Murph, Giang H. Nguyen, Harish Radhakrishna, Gordon B. Mills

    Research output: Contribution to journalReview article

    40 Scopus citations

    Abstract

    Since the molecular cloning of the vzg-1/Edg-2/LPA1 gene, studies have attempted to characterize LPA1 receptor functionality into a single categorical role, different from the other Edg-family LPA receptors. The desire to categorize LPA1 function has highlighted its complexity and demonstrated that the LPA1 receptor does not have one absolute function throughout every system. The central nervous system is highly enriched in the LPA1 receptor, suggesting an integral role in neuronal processes. Metastatic and invasive breast cancer also appears to have LPA-mediated LPA1 receptor functions that enhance phenotypes associated with tumorigenesis. LPA1 possesses a number of motifs conserved among G protein-coupled receptors (GPCRs): a DRY-like motif, a PDZ domain, Ser/Thr predicted sites of phosphorylation, a di-leucine motif, double cysteines in the tail and conserved residues that stabilize structure and determine ligand binding. The third intracellular loop of the LPA1 receptor may be the crux of receptor signaling and attenuation with phosphorylation of Thr-236 potentially a key determinant of basal LPA1 signaling. Mutagenesis data supports the notion that Thr-236 regulates this process since mutating Thr-236 to Ala-236 increased basal and LPA-mediated serum response factor (SRF) signaling activity and Lys-236 further increased this basal signaling. Here we describe progress on defining the major functions of the LPA1 receptor, discuss a context dependent dualistic role as both a negative regulator in cancer and a proto-oncogene, outline its structural components at the molecular amino acid level and present mutagenesis data on the third intracellular loop of the receptor.

    Original languageEnglish (US)
    Pages (from-to)547-557
    Number of pages11
    JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
    Volume1781
    Issue number9
    DOIs
    StatePublished - Sep 1 2008

    Keywords

    • AKT
    • Breast cancer
    • ICL3
    • LPA
    • LPA1 receptor
    • Mutagenesis
    • Ovarian cancer

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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