Integrin α5β1 Function Is Regulated by XGIPC/kermit2 Mediated Endocytosis during Xenopus laevis Gastrulation

Spicer, Erin; Suckert, Catherine; Al-Attar, Hyder; Marsden, Mungo

doi:10.1371/journal.pone.0010665

Cited by 14 publications

(17 citation statements)

References 58 publications

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“…In endothelial cells, recruitment of active a5b1 integrin to the neuropilin-GIPC1 (for GAIP C-terminus-interacting protein) complex regulates endocytosis of this integrin directly from fibrillar adhesions (Valdembri et al, 2009). Xenopus GIPC1 (also known as kermit2) regulates a5b1 integrin internalisation into Rab21-positive vesicles (Spicer et al, 2010), which suggests that mechanisms that regulate integrin internalisation are conserved.…”

Section: Mechanisms Of Integrin Endocytosismentioning

confidence: 99%

Integrin trafficking at a glance

Bridgewater

Norman

Caswell

2012

Journal of Cell Science

175

167

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Section: Mechanisms Of Integrin Endocytosismentioning

confidence: 99%

Integrin trafficking at a glance

Bridgewater

Norman

Caswell

2012

Journal of Cell Science

175

167

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“…As integrins are mechano-sensory receptors that bridge extracellular matrix and cytoplasmic adaptor proteins associated with actin filaments, integrin recycling to cell surface is required for the regulation of actin dynamisms. 59, 60 Indeed, GIPC1 is required for the trafficking of internalized integrins during cell migration, 19 angiogenesis 61 and cytokinesis. 15 …”

Section: Intracellular Functions Of Gipc1mentioning

confidence: 99%

“…17 Kermit 2 also interacts with the integrin α5 subunit to regulate endocytosis of α5β1 integrin, which is essential for the lining of the fibronectin matrix on the blastocoel roof during the gastrulation stage of embryogenesis. 19 …”

Section: Evolutionarily Conservation Of Gipcsmentioning

confidence: 99%

“…1, 2, 3, 4, 16, 17, 18, 19, 20, 21, 22, 23, 24 GIPCs are involved in the trafficking of various transmembrane proteins and regulate a variety of cellular processes, such as proliferation, planar cell polarity, cytokinesis and migration. Pathologies associated with the GIPCs, such as hearing loss 11, 12 and cancer, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 are emerging topics in the medical sciences.…”

Section: Introductionmentioning

confidence: 99%

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Functional proteomics, human genetics and cancer biology of GIPC family members

Katoh

2013

Exp Mol Med

123

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GIPC1, GIPC2 and GIPC3 consist of GIPC homology 1 (GH1) domain, PDZ domain and GH2 domain. The regions around the GH1 and GH2 domains of GIPC1 are involved in dimerization and interaction with myosin VI (MYO6), respectively. The PDZ domain of GIPC1 is involved in interactions with transmembrane proteins [IGF1R, NTRK1, ADRB1, DRD2, TGFβR3 (transforming growth factorβ receptor type III), SDC4, SEMA4C, LRP1, NRP1, GLUT1, integrin α5 and VANGL2], cytosolic signaling regulators (APPL1 and RGS19) and viral proteins (HBc and HPV-18 E6). GIPC1 is an adaptor protein with dimerizing ability that loads PDZ ligands as cargoes for MYO6-dependent endosomal trafficking. GIPC1 is required for cell-surface expression of IGF1R and TGFβR3. GIPC1 is also required for integrin recycling during cell migration, angiogenesis and cytokinesis. On early endosomes, GIPC1 assembles receptor tyrosine kinases (RTKs) and APPL1 for activation of PI3K–AKT signaling, and G protein-coupled receptors (GPCRs) and RGS19 for attenuation of inhibitory Gα signaling. GIPC1 upregulation in breast, ovarian and pancreatic cancers promotes tumor proliferation and invasion, whereas GIPC1 downregulation in cervical cancer with human papillomavirus type 18 infection leads to resistance to cytostatic transforming growth factorβ signaling. GIPC2 is downregulated in acute lymphocytic leukemia owing to epigenetic silencing, while Gipc2 is upregulated in estrogen-induced mammary tumors. Somatic mutations of GIPC2 occur in malignant melanoma, and colorectal and ovarian cancers. Germ-line mutations of the GIPC3 or MYO6 gene cause nonsyndromic hearing loss. As GIPC proteins are involved in trafficking, signaling and recycling of RTKs, GPCRs, integrins and other transmembrane proteins, dysregulation of GIPCs results in human pathologies, such as cancer and hereditary deafness.

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“…gipc2 morphants have an eye phenotype similar to that of the eif6 gain-of-function embryos (Wu et al, 2006;De Marco et al, in preparation). It should be mentioned that the gipc2 protein is a powerful modulator of signals as it interacts not only with igfr but also with a variety of molecules implicated in cell signalling, such as semaphorins-F and 4C (Wang et al, 1999), and integrins (Spicer et al, 2010) (see Wu et al, 2006, for detailed references).…”

mentioning

confidence: 99%

Involvement of the eukaryotic initiation factor 6 and kermit2/gipc2 in Xenopus laevis pronephros formation

Tussellino¹,

Marco²,

Campanella³

et al. 2012

Int. J. Dev. Biol.

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The translation initiation factor Eif6 has been implicated as a regulator of ribosome assembly, selective mRNA translation and apoptosis. Many of these activities depend upon the phosphorylation of eif6 Serine 235 by protein kinase C (PKC). Eif6-60S is probably part of the RNAinduced silencing complex (RISC). eif6 over-expression in Xenopus embryos causes aberrant eye development. kermit2/gipc2 morphants have an eye phenotype similar to that of the eif6 overexpressors. Eye formation is regulated by insulin growth factor (IGF) signalling. eif6 interacts with the IGF receptor (IGFR) and kermit2/gipc2, which also binds to igfr. eif6 over-expression in Xenopus causes also the formation of antero-ventral oedema, suggesting a malfunction of the excretory system. Here we evaluated the pronephros phenotype. The oedema grows into the nephrocoel, expanding its boundary and is accompanied by a strong reduction of the pronephros. The three main components of the pronephros are severely impaired in eif6 over-expressors, while are not affected in eif6 morphants. Conversely, gipc2 depletion induces the oedema phenotype and reduction of the pronephros, while gipc2 overexpression does not. p110*, a constitutively active p110 subunit of the PI3 kinase partially recovers the oedema phenotype. We also determined that PKC-dependent phosphorylation of Ser235 in eif6 is not required to produce defective pronephroi. These results indicate that the levels of eif6 are highly regulated during development and instrumental for proper morphogenesis of the pronephros. Moreover, it appears that for proper pronephros development the gipc2 level should be kept within or over the physiological range and that the oedema phenotype is partly due to the inhibition of IGF signalling. KEY WORDS: pronephros, Xenopus laevis, eukaryotic initiation factor 6, kermit2/gipc2Eif6 1 (eukaryotic initiation factor 6) is a protein essential for cell survival that plays important roles in ribosome biogenesis and translation (see Ceci et al., 2003). In particular, it is associated with the plasma membrane where it interacts with b4 integrin as well as the cytoskeleton (Biffo et al., 1997). Eif6 can be regulated by extracellular signals, such as IGF (Gandin et al., 2008), and is itself a regulator of translation at the 60S ribosomal subunit. When unphosphorylated, it impedes the joining of the 60S with the 40S ribosomal subunit. When phosphorylated by PKC, Eif6 separates from the 60S subunit. As a consequence, ribosomal subunits 60S and 40S may join, allowing mRNA translation to occur (Ceci et al., 2003). Eif6-60S is probably part of the RISC (RNA-induced silencing complex) and as such may regulate the availability of mRNAs for translation (Chendrimada et al., 2007). Because EIF6 appears to act selectively on specific mRNAs (Ji Abbreviations used in this paper: Akt, serine/threonine-protein kinase; bgal, bgalactosidase; Clcnk , chloride channel Kb; cdh16 , human cadherin-16; Eif6 1 , eukaryotic initiation factor 6; IGF, insulin growth factor; Igfr, insulin g...

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Integrin α5β1 Function Is Regulated by XGIPC/kermit2 Mediated Endocytosis during Xenopus laevis Gastrulation

Cited by 14 publications

References 58 publications

Integrin trafficking at a glance

Integrin trafficking at a glance

Functional proteomics, human genetics and cancer biology of GIPC family members

Involvement of the eukaryotic initiation factor 6 and kermit2/gipc2 in Xenopus laevis pronephros formation

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