Emerging roles for the FSH receptor adapter protein APPL1 and overlap of a putative 14-3-3τ interaction domain with a canonical G-protein interaction site.
The interaction of cytoplasmic proteins with intracellular domains of membrane receptors can occur at several opportunities, including: during biosynthesis, while in membrane residency and during internalization and recycling following ligand binding. Since the initial discovery that it interacts with the FSH receptor (FSHR) together with additional members of a potential signaling complex, APPL1 has been shown to interact with a variety of membrane receptors. Recent subcellular localizations of APPL1 place it in dynamic and varied venues in the cell, including at the cell membrane, the nucleus and the early endosomes. Another adapter protein family the 14-3-3 proteins, are largely recognized as binding to phosphorylation sites but recent work demonstrated that in the case of FSHR, the 14-3-3 site overlaps with the canonical G-protein binding site. G-proteins appear to sample the environment and exchange between the membrane and intracellular locales and this binding could be mediated by or modulated by receptor interactions at the 14-3-3 binding site. Observations that multiple proteins can interact with cytoplasmic domains of GPCRs leads to the inescapable conclusion that either the interactions occur via orderly replacement or exchange, or that receptors are simultaneously occupied by a variety of adapters and effectors or even that oligomers of dimeric GPCRs provide for platforms that can simultaneously interact with effectors and adaptors.
Dias
James A
JA
Wadsworth Center, New York State Dept of Health, Albany, NY, United States. james.dias@wadsworth.org
Mahale
Smita D
SD
Nechamen
Cheryl A
CA
Davydenko
Olga
O
Thomas
Richard M
RM
Ulloa-Aguirre
Alfredo
A
D048948:14-3-3 Proteins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D001665:Binding Sites; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D011962:Receptors, FSH
D048948:14-3-3 Proteins; C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D011962:Receptors, FSH; D019204:GTP-Binding Proteins