The PDZ Protein GIPC Regulates Trafficking of the LPA1 Receptor from APPL Signaling Endosomes and Attenuates the Cell’s Response to LPA

Abstract

Lysophosphatidic acid (LPA) mediates diverse cellular responses through the activation of at least six LPA receptors – LPA1–6, but the interacting proteins and signaling pathways that mediate the specificity of these receptors are largely unknown. We noticed that LPA1 contains a PDZ binding motif (SVV) identical to that present in two other proteins that interact with the PDZ protein GIPC. GIPC is involved in endocytic trafficking of several receptors including TrkA, VEGFR2, lutropin and dopamine D2 receptors. Here we show that GIPC binds directly to the PDZ binding motif of LPA1 but not that of other LPA receptors. LPA1 colocalizes and coimmunoprecipitates with GIPC and its binding partner APPL, an activator of Akt signaling found on APPL signaling endosomes. GIPC depletion by siRNA disturbed trafficking of LPA1 to EEA1 early endosomes and promoted LPA1 mediated Akt signaling, cell proliferation, and cell motility. We propose that GIPC binds LPA1 and promotes its trafficking from APPL-containing signaling endosomes to EEA1 early endosomes and thus attenuates LPA-mediated Akt signaling from APPL endosomes.

The MYO6 interactome reveals adaptor complexes coordinating early endosome and cytoskeletal dynamics

“…Interestingly, LARG has previously been linked to signalling from GPCRs such as the lysophosphatidic acid receptor (LPAR1), that is also trafficked by GIPC1 and MYO6 through APPL1 endosomes (Figs 4A and B, and EV3A) 31, 32, 33. We therefore determined whether the MYO6‐GIPC1‐LARG‐SH3BP4 complex links LARG and RHO‐dependent actin organisation to GIPC1 endosome function and position.…”

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…During development, expression of Lpar2 is more diffuse than Lpar1, although it is clearly present in the embryonic pathways are being uncovered. Toward elucidating these interactions, one study demonstrated that LPA 1 (but not other tested LPA receptors) is traffi cked to early endosomes through a PDZ-mediated motif that facilitates its binding to GAIP interacting protein, C-terminus (GIPC), which attenuates LPA-mediated Akt signaling from adaptor protein containing PH domain (APPL) signaling endosomes (109). Other studies identifi ed LPA as a critical regulator of the Hippo-Yes-associated protein (YAP) pathway, which controls LPA-induced gene expression, cell migration, and cell proliferation.…”

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

“…Furthermore, GIPC expression suppresses dopamine 3 receptor Ga i -coupling and prevents dopamine 3 receptor degradation (Jeanneteau et al, 2004). GIPC also plays a role in regulating both the human luteinizing hormone receptor and LPA 1 R trafficking (Hirakawa et al, 2003;Varsano et al, 2012). The interaction of GIPC with LPA 1 R is essential for LPA 1 R trafficking from APPL-positive signaling endosomes to early endosome antigen 1-positive early endosomes (Varsano et al, 2012).…”

“…GIPC also plays a role in regulating both the human luteinizing hormone receptor and LPA 1 R trafficking (Hirakawa et al, 2003;Varsano et al, 2012). The interaction of GIPC with LPA 1 R is essential for LPA 1 R trafficking from APPL-positive signaling endosomes to early endosome antigen 1-positive early endosomes (Varsano et al, 2012). Additionally, GIPC links LPA 1 R to the protein kinase B signaling pathway, cell proliferation, and cell motility (Varsano et al, 2012).…”

“…The interaction of GIPC with LPA 1 R is essential for LPA 1 R trafficking from APPL-positive signaling endosomes to early endosome antigen 1-positive early endosomes (Varsano et al, 2012). Additionally, GIPC links LPA 1 R to the protein kinase B signaling pathway, cell proliferation, and cell motility (Varsano et al, 2012). GIPC also contributes to the suppression of b 1 ARmediated ERK activation, but does affect b 1 AR-stimulated cAMP accumulation (Hu et al, 2003).…”