NCBI Summary:
The protein encoded by this gene has been shown to be involved in the regulation of cell proliferation, and in the crosstalk between the adiponectin signalling and insulin signalling pathways. The encoded protein binds many other proteins, including RAB5A, DCC, AKT2, PIK3CA, adiponectin receptors, and proteins of the NuRD/MeCP1 complex. This protein is found associated with endosomal membranes, but can be released by EGF and translocated to the nucleus. [provided by RefSeq, Jul 2008]
General function
Intracellular signaling cascade
Comment
Cellular localization
Plasma membrane
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APPL1 as an important regulator of insulin and adiponectin signaling pathways in the PCOS: A narrative review. Artimani T et al. (2020) Adaptor protein containing a PH domain, PTB domain and leucine zipper motif 1 (APPL1) plays a central role as the main contributing factor in the adiponectin and insulin signaling. This review aims to discuss previous and recent findings concerning the role of APPL1 in the polycystic ovary syndrome (PCOS) patients with conclusions regarding more efficient therapeutic approaches. A literature review was performed in PubMed, Web of Science, ScienceDirect, Scopus and, Google Scholar from Aug 1999 to May 2020. This study reveals APPL1 has a key role in adiponectin, insulin, and follicle-stimulating hormone (FSH) signaling pathways occurring within the ovaries. Recent studies in mouse model systems have indicated that APPL1 can prevent diabetes, endothelial disorders, and insulin resistance. In contrast, APPL1 deficiency can lead to the metabolic and vascular disorders. APPL1 due to its potential roles in different signaling pathways might be suggested as a novel diagnostic and therapeutic option for prediction of ovarian dysfunctions, and treatment of reproductive disorders especially PCOS. This article is protected by copyright. All rights reserved.//////////////////
Ovarian function
Comment
The Adapter Protein APPL1 Links FSH Receptor to Inositol 1,4,5-Trisphosphate Production and Is Implicated in Intracellular Ca2+ Mobilization. Thomas RM et al. FSH binds to its receptor (FSHR) on target cells in the ovary and testis, to regulate oogenesis and spermatogenesis, respectively. The signaling cascades activated after ligand binding are extremely complex and have been shown to include protein kinase A, mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B, and inositol 1,4,5-trisphosphate-mediated calcium signaling pathways. The adapter protein Pleckstrin homology domain, Phosphotyrosine binding domain, and Leucine zipper motif (APPL1), which has been linked to an assortment of other signaling proteins, was previously identified as an interacting protein with FSHR. Thus, alanine substitution mutations in the first intracellular loop of FSHR were generated to determine which residues are essential for FSHR-APPL1 interaction. Three amino acids were essential; when any one of them was altered, APPL1 association with FSHR mutants was abrogated. Two of the mutants (L377A and F382A) that displayed poor cell-surface expression were not studied further. Substitution of FSHR-K376A did not affect FSH binding or agonist-stimulated cAMP production in either transiently transfected human embryonic kidney cells or virally transduced human granulosa cells (KGN). In the KGN line, as well as primary cultures of rat granulosa cells transduced with wild type or mutant receptor, FSH-mediated progesterone or estradiol production was not affected by the mutation. However, in human embryonic kidney cells inositol 1,4,5-trisphosphate production was curtailed and KGN cells transduced with FSHR-K376A evidenced reduced Ca(2+) mobilization from intracellular stores after FSH treatment.
Expression regulated by
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Ovarian localization
Granulosa
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Expression of follicle-stimulating hormone receptor (FSHR), protein kinase B-2 (AKT2) and adapter protein with PH domain, PTB domain, and leucine zipper (APPL1) in pig ovaries. Zhou N et al. (2018) Follicle-stimulating hormone (FSH) regulates oogenesis and spermatogenesis by binding to its receptor (FSHR) on target cells in the ovary and testis, respectively. The signaling cascades activated after ligand binding are extremely complex and have been shown to include protein kinase A and phosphatidylinositol 3-kinase/protein kinase. The adapter protein APPL1 (adapter protein with PH domain, PTB domain, and leucine zipper), which is an assortment of other signaling proteins, was previously identified to interact with the FSH receptor (FSHR) and the protein kinase B (AKT) pathway. APPL1 plays an important role in promoting cell survival within the preovulatory follicle granulosa layer. Here, we aimed to evaluate the FSHR, AKT2, and APPL1 gene and protein expression levels in the ovaries of different prolific porcine breeds (Wannan Black WB] and Large White [LW] pigs) using immunohistochemistry and qRT-PCR, respectively. Our results showed that FSHR, AKT2, and APPL1 mRNA levels were significantly higher (P < 0.05) in the ovaries of WB pigs than in the ovaries of LW pigs. Additionally, the FSHR, AKT2, and APPL1 proteins were mainly found distributed in the granulosa cells and oocytes. This study showed that high levels of FSHR, AKT2, and APPL1 were expressed in the ovaries of high prolific breed pigs.//////////////////
Emerging Roles for the FSH Receptor Adapter Protein APPL1 and Overlap of a Putative 14-3-3tau Interaction Domain with a Canonical G-protein Interaction Site. [Dias JA et al. 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.