Kermit 2/XGIPC, an IGF1 receptor interacting protein, is required for IGF signaling in Xenopus eye development

William Penn University, Filadelfia, Pennsylvania, United States
Development (Impact Factor: 6.46). 10/2006; 133(18):3651-60. DOI: 10.1242/dev.02547
Source: PubMed


GIPC is a PDZ-domain-containing protein identified in vertebrate and invertebrate organisms through its interaction with a variety of binding partners including many membrane proteins. Despite the multiple reports identifying GIPC, its endogenous function and the physiological significance of these interactions are much less studied. We have previously identified the Xenopus GIPC homolog kermit as a frizzled 3 interacting protein that is required for frizzled 3 induction of neural crest in ectodermal explants. We identified a second Xenopus GIPC homolog, named kermit 2 (also recently described as an IGF receptor interacting protein and named XGIPC). Despite its high amino acid similarity with kermit, kermit 2/XGIPC has a distinct function in Xenopus embryos. Loss-of-function analysis indicates that kermit 2/XGIPC is specifically required for Xenopus eye development. Kermit 2/XGIPC functions downstream of IGF in eye formation and is required for maintaining IGF-induced AKT activation. A constitutively active PI3 kinase partially rescues the Kermit 2/XGIPC loss-of-function phenotype. Our results provide the first in vivo loss of function analysis of GIPC in embryonic development and also indicate that kermit 2/XGIPC is a novel component of the IGF pathway, potentially functioning through modulation of the IGF1 receptor.

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    • "Whereas the overexpression of Kermit 2 does also not affect eye development (as did not IRS-1), the loss of Kermit 2 specifically inhibits eye formation through down-regulation of the PI-3K/Akt pathway. Importantly no other anterior neural structures were affected (Wu et al., 2006). "
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    ABSTRACT: Extracellular signal transduction into cells through ligand-activated receptor tyrosine kinases, such as insulin-like growth factor-1 (IGF-1) receptor (IGF-1R) and insulin receptor (IR) is required for normal embryonic growth and development. The major mediators of IR and IGF-1R are adaptor proteins of the insulin receptor substrate family, the best characterized member of which is IRS-1. Insulin receptor substrate IRS-1 has been shown to influence cell and body size and to interfere with differentiation. We have isolated IRS-1 from Xenopus laevis embryos and analyzed for the first time its spatial and temporal expression pattern during embryogenesis. We found that Xenopus IRS-1 is expressed maternally and constantly during embryogenesis. It is predominantly found in neural tissue at different stages. Furthermore, knock down of IRS-1 in neural tissue by specific antisense morpholino oligonucleotides (MO) resulted in abnormal eye formation accompanied by reduction of the eye-specific marker genes Rx1 and Pax6 and a decreased cell proliferation.
    Preview · Article · Jul 2011 · Developmental Dynamics
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    • "Previous publications using morpholino knockdowns did not describe an early role for kermit2 in Xenopus development. However, it is clear in these studies that MO knockdowns produce a variety of phenotypes in morphant embryos, including deficits in axial extension [26]. Our experiments with morpholinos also demonstrate there is considerable variation in the axial extension of morphant embryos, although the defects in anterior neural and eye development are always robust. "
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    ABSTRACT: During Xenopus gastrulation alpha5beta1 integrin function is modulated in a temporally and spatially restricted manner, however, the regulatory mechanisms behind this regulation remain uncharacterized. Here we report that XGIPC/kermit2 binds to the cytoplasmic domain of the alpha5 subunit and regulates the activity of alpha5beta1 integrin. The interaction of kermit2 with alpha5beta1 is essential for fibronectin (FN) matrix assembly during the early stages of gastrulation. We further demonstrate that kermit2 regulates alpha5beta1 integrin endocytosis downstream of activin signaling. Inhibition of kermit2 function impairs cell migration but not adhesion to FN substrates indicating that integrin recycling is essential for mesoderm cell migration. Furthermore, we find that the alpha5beta1 integrin is colocalized with kermit2 and Rab 21 in embryonic and XTC cells. These data support a model where region specific mesoderm induction acts through kermit2 to regulate the temporally and spatially restricted changes in adhesive properties of the alpha5beta1 integrin through receptor endocytosis.
    Preview · Article · May 2010 · PLoS ONE
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    • "APPL was initially identified as an interactor of Akt, and further linked to signaling by its ability to bind to numerous receptors, either directly or via the small PDZ-containing adaptor GIPC (Hu et al., 2003; Lin et al., 2006; Mao et al., 2006; Wu et al., 2006). Accordingly, some colocalization of APPL with Akt was reported (Schenck et al., 2008). "
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    ABSTRACT: The recent identification of several novel endocytic compartments has challenged our current understanding of the topological and functional organization of the endocytic pathway. Using quantitative single vesicle imaging and acute manipulation of phosphoinositides we show that APPL endosomes, which participate in growth factor receptor trafficking and signaling, represent an early endocytic intermediate common to a subset of clathrin derived endocytic vesicles and macropinosomes. Most APPL endosomes are precursors of classical PI3P positive endosomes, and PI3P plays a critical role in promoting this conversion. Depletion of PI3P causes a striking reversion of Rab5 positive endosomes to the APPL stage, and results in enhanced growth factor signaling. These findings reveal a surprising plasticity of the early endocytic pathway. Importantly, PI3P functions as a switch to dynamically regulate maturation and signaling of APPL endosomes.
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