Receptor Tyrosine Kinase Ubiquitylation Involves the Dynamic Regulation of Cbl-Spry2 by Intersectin 1 and the Shp2 Tyrosine Phosphatase

Okur, Mustafa Nazir; Russo, Angela; O’Bryan, John P.

doi:10.1128/mcb.00850-13

Cited by 16 publications

(18 citation statements)

References 40 publications

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“…By combining miRNA and mRNA microarray results, of all the seven predicted target genes of miR‐122‐5p, we selected Sprouty2 for further study. Sprouty2 (Spry2) belongs to a member of highly conserved Sprouty signal transduction proteins family, whose unique carboxyl‐terminal cysteine‐rich domain is essential for the inhibition of receptor tyrosine kinase signalling . As an inhibitor of the Erk/MAPK signalling pathway, it is required for growth factors stimulated translocation to membrane ruffles and interacts with various early MAPK pathway‐associated proteins that play an important role in cell proliferation, differentiation and migration .…”

Section: Discussionmentioning

confidence: 99%

IL‐22‐induced miR‐122‐5p promotes keratinocyte proliferation by targeting Sprouty2

Jiang

Gao

et al. 2017

Experimental Dermatology

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Psoriasis is a common inflammatory skin disease, but the exact pathogenesis is largely unknown. Interleukin-22 (IL-22) has demonstrated its vital role in T-cell-mediated immune response by interacting with keratinocytes in the pathogenesis of psoriasis. Here, we showed the differentially expressed miRNAs and their potential targets in HaCaT cells stimulated by IL-22 using miRNA and mRNA microarrays. We revealed a total of 20 significantly changed (more than twofold) miRNAs in HaCaT cells and validated the results with quantitative reverse transcriptase PCR (qRT-PCR). We demonstrated that miR-122-5p was up-regulated both in HaCaT cells stimulated by IL-22 and in psoriatic lesions. Then, we aimed to investigate the biological roles and potential mechanism of miR-122-5p in keratinocytes. As a result, CCK-8 assay indicated that overexpression of miR-122-5p in keratinocytes promoted proliferation and conversely inhibition of endogenous miR-122-5p suppressed proliferation. According to the microarray analysis, we assumed that Sprouty2 (Spry2), a negative regulator of extracellular signal regulated kinase/mitogen-activated protein kinase signalling pathway, was a direct target gene of miR-122-5p. We found that the staining of Spry2 in cytoplasm was mainly localized in both basal and suprabasal layers of epidermis and showed a markedly decreased expression in psoriasis than in normal control by immunohistochemistry. Luciferase reporter and Western blot assays in HaCaT cells demonstrated that Spry2 was a direct target gene of miR-122-5p. In conclusion, IL-22-induced miR-122-5p promotes keratinocyte proliferation possibly by downregulating the expression of Spry2 thus playing important roles in the pathogenesis of psoriasis.

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Section: Discussionmentioning

confidence: 99%

IL‐22‐induced miR‐122‐5p promotes keratinocyte proliferation by targeting Sprouty2

Jiang

Gao

et al. 2017

Experimental Dermatology

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“…5F), whereas earlier reports have shown that Spry2 dominant-negative mutant unable to bind c-Cbl did not function as dominant-negative form and kept EGFR levels unchanged Haglund et al, 2005]. Although the precise mechanism through which Y55A-Spry2 suppresses endogenous Spry2 and c-Cbl interaction remains unclear, it was recently reported that intersectin1 (ITSN1), which stimulates ubiquination of EGFR through enhancing the activity of Cbl, interacts with and recruits the Shp2 tyrosine phosphatase to Spry2 to enhance its dephosphorylation, thereby disrupting the inhibitory effect of Spry2 on Cbl and increasing EGFR ubiquitination [Okur et al, 2014]. While our results indicate that Y55A-Spry2 enhances EGFR ubiquitination and degradation, our data do not address the functional consequences of this Spry2-Cbl complex and Y55A-Spry2 interaction.…”

Section: Discussionmentioning

confidence: 99%

Mutation of Spry2 Induces Proliferation and Differentiation of Osteoblasts but Inhibits Proliferation of Gingival Epithelial Cells

Sanui

Tanaka

Fukuda

et al. 2015

J of Cellular Biochemistry

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Sprouty was identified as an inhibitor of the fibroblast growth factor (FGF) receptor, and Sprouty2 (Spry2) functions as a negative regulator of receptor tyrosine kinase signaling. In this study, we investigated how inhibition of Spry2 affects osteoblasts and gingival epithelial cells in periodontal tissue regeneration in vitro. Transduction of a dominant-negative mutant of Spry2 (Y55A-Spry2) enhanced basic fibroblast growth factor (bFGF)- and epidermal growth factor (EGF)-induced ERK activation in MC3T3-E1 osteoblastic cells. In contrast, it decreased their activation in GE1 cells. Consistent with these observations, Y55A-Spry2 increased osteoblast proliferation with bFGF and EGF stimulation, whereas the proliferation of Y55A-Spry2-introduced GE1 cells was decreased via the ubiquitination and degradation of EGF receptors (EGFRs). In addition, Y55A-Spry2 caused upregulation of Runx2 expression and downregulation of Twist, a negative regulator of Runx2, with treatment of bFGF and EGF, resulting in enhanced osteoblastogenesis accompanied by alkaline phosphatase activation and osteocalcin expression in MC3T3-E1 cells. These data suggest that suppression of Spry2 expression induces proliferation and differentiation of osteoblastic cells after the addition of a bFGF and EGF cocktail but inhibits proliferation in gingival epithelial cells. These in vitro experiments may provide a molecular basis for novel therapeutic approaches in periodontal tissue regeneration. Taken together, our study proposes that combined application of an inhibitor for tyrosine 55 of Spry2, bFGF, and EGF may effectively allow alveolar bone growth and block the ingrowth of gingival epithelial cells toward bony defects, biologically mimicking a barrier effect in guided tissue regeneration, with in vivo investigation in the future.

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“…dynamin and synaptojanin) [1, 9, 10], actin rearrangement (e.g. N-WASP) [11], cell survival (e.g., PI3KC2β) [12], and cell signaling (e.g., Sos, Cbl, and RALT) [13–16] (reviewed in [2, 7, 17]). Some ITSN orthologs in lower eukaryotes have fewer SH3 domains.…”

Section: Structure and Subcellular Localizationmentioning

confidence: 99%

“…ITSN activates Cbl through a complex network of protein:protein interactions. In addition to binding Cbl, ITSN binds Spry2, a Cbl inhibitor, and the tyrosine phosphatase Shp2, a Cbl activator [16, 60]. These interactions lead to decreased tyrosine phosphorylation of Spry2, which disrupts binding to Cbl’s N-terminal SH2-like domain, thereby resulting in Cbl activation.…”

Section: Functionmentioning

confidence: 99%

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Intersectin scaffold proteins and their role in cell signaling and endocytosis

Herrero-Garcia

O’Bryan

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Intersectins (ITSNs) are a family of multi-domain proteins involved in regulation of diverse cellular pathways. These scaffold proteins are well known for regulating endocytosis but also play important roles in cell signaling pathways including kinase regulation and Ras activation. ITSNs participate in several human cancers, such as neuroblastomas and glioblastomas, while its downregulation is associated with lung injury. Alterations in ITSN expression have been found in neurodegenerative diseases such as Down Syndrome and Alzheimer’s disease. Binding proteins for ITSNs include endocytic regulatory factors, cytoskeleton related proteins (i.e. actin or dynamin), signaling proteins as well as herpes virus proteins. This review will summarize recent studies on ITSNs, highlighting the importance of these scaffold proteins in the aforementioned processes.

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Receptor Tyrosine Kinase Ubiquitylation Involves the Dynamic Regulation of Cbl-Spry2 by Intersectin 1 and the Shp2 Tyrosine Phosphatase

Cited by 16 publications

References 40 publications

IL‐22‐induced miR‐122‐5p promotes keratinocyte proliferation by targeting Sprouty2

IL‐22‐induced miR‐122‐5p promotes keratinocyte proliferation by targeting Sprouty2

Mutation of Spry2 Induces Proliferation and Differentiation of Osteoblasts but Inhibits Proliferation of Gingival Epithelial Cells

Intersectin scaffold proteins and their role in cell signaling and endocytosis

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