Kermit 2/XGIPC, an IGF1 receptor interacting protein, is required for IGF signaling in Xenopus eye development
ABSTRACT 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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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.Developmental Dynamics 07/2011; 240(7):1705-15. DOI:10.1002/dvdy.22659 · 2.67 Impact Factor
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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.Cell 04/2009; 136(6):1110-21. DOI:10.1016/j.cell.2009.01.032 · 33.12 Impact Factor
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ABSTRACT: The trafficking of receptor tyrosine kinases (RTKs) to distinct subcellular locations is essential for the specificity and fidelity of signal transduction and biological responses. This is particularly important in the PNS and CNS in which RTKs mediate key events in the development and maintenance of neurons and glia through a wide range of neural processes, including survival, proliferation, differentiation, neurite outgrowth, and synaptogenesis. The mechanisms that regulate the targeting of RTKs to their subcellular destinations for appropriate signal transduction, however, are still elusive. In this review, we discuss evidence for the spatial organization of signaling machinery into distinct subcellular compartments, as well as the role for ligand specificity, receptor sorting signals, and lipid raft microdomains in RTK targeting and the resultant cellular responses in neural cells.Journal of Neurochemistry 04/2008; 105(6):2055-68. DOI:10.1111/j.1471-4159.2008.05263.x · 4.24 Impact Factor