The ErbB-4 s80 intracellular domain is a constitutively active tyrosine kinase

Linggi, Bryan; Cheng, Qiu-chen; Rao, Anurada; Carpenter, Graham

doi:10.1038/sj.onc.1209003

Cited by 52 publications

(51 citation statements)

References 31 publications

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“…The resulting 'kinase-dead' ICD2 K751R mutant did not demonstrate autophosphorylation when analysed by antiphosphotyrosine Western blotting (Figure 4b), consistent with a recent report of a similar ICD2 construct (Linggi et al, 2006). Nuclear translocation of ICD2 K751R was also impaired as analysed by confocal microscopy ( Figure 4c) and quantitation of microscopy data for statistical analysis (Figure 4d).…”

Section: Erbb4 Icds Differ In Subcellular Localizationsupporting

confidence: 73%

Differential nuclear localization and kinase activity of alternative ErbB4 intracellular domains

et al. 2007

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Cleavable isoforms of the ErbB4 receptor tyrosine kinase release a soluble intracellular domain (ICD) that may translocate to the nucleus and regulate signaling. However, ErbB4 gene is alternatively spliced generating CYT-1 and CYT-2 isoforms with different cytoplasmic tails. Here, we addressed whether the two alternative ErbB4 ICDs of either CYT-1 (ICD1) or CYT-2 (ICD2) type differ in signaling to the nucleus. Confocal microscopy and extraction of nuclear cell fractions indicated that significantly more ICD2 translocated to the nuclei when compared to ICD1. Unlike the membrane-anchored 80 kDa fragments derived from full-length ErbB4 isoforms, the two ICDs did not differ from each other in metabolic stability or ubiquitylation. However, ICD2 was phosphorylated at tyrosine residues to a higher extent and demonstrated greater in vitro kinase activity than ICD1. Mutating the ATP-binding site within ICD2 kinase domain (ICD2 K751R) blocked its tyrosine phosphorylation and significantly reduced its nuclear translocation. When expressed in the context of full-length ErbB4, ICD2 was also more efficient than ICD1 in promoting transcriptional activation of the STAT5 target gene b-casein. These findings indicate that the two alternative ICDs of ErbB4 differ in their nuclear accumulation, and that the mechanism involves differential kinase activity but not ubiquitin-regulated ICD stability.

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Section: Erbb4 Icds Differ In Subcellular Localizationsupporting

confidence: 73%

Differential nuclear localization and kinase activity of alternative ErbB4 intracellular domains

et al. 2007

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“…This showed increased tyrosine phosphorylation of a major 180-kDa band, the expected size of ErbB4, and a less prominent 80-kDa band in TC32 and TC71 spheroids versus monolayers. Activated ErbB4 can be proteolytically cleaved to generate a soluble 80-kDa cytosolic fragment, ErbB4-s80, which retains tyrosine kinase activity (36)(37)(38), and we hypothesized that the 80-kDa band represents ErbB4-s80. Western blots of input lysates using total ErbB4 antibodies showed similar expression of the 180-kDa ErbB4 protein in spheroids versus monolayers, whereas the 80-kDa band was not readily apparent (Fig.…”

Section: Resultsmentioning

confidence: 99%

E-Cadherin Cell-Cell Adhesion in Ewing Tumor Cells Mediates Suppression of Anoikis through Activation of the ErbB4 Tyrosine Kinase

et al. 2007

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Ability to grow under anchorage-independent conditions is one of the major hallmarks of transformed cells. Key to this is the capacity of cells to suppress anoikis, or programmed cell death induced by detachment from the extracellular matrix. To model this phenomenon in vitro, we plated Ewing tumor cells under anchorage-independent conditions by transferring them to dishes coated with agar to prevent attachment to underlying plastic. This resulted in marked up-regulation of E-cadherin and rapid formation of multicellular spheroids in suspension. Addition of calcium chelators, antibodies to E-cadherin (but not to other cadherins or B 1 -integrin), or expression of dominant negative E-cadherin led to massive apoptosis of spheroid cultures whereas adherent cultures were unaffected. This correlated with reduced activation of the phosphatidylinositol 3-kinase-Akt pathway but not the Rasextracellular signal-regulated kinase 1/2 cascade. Furthermore, spheroid cultures showed profound chemoresistance to multiple cytotoxic agents compared with adherent cultures, which could be reversed by A-E-cadherin antibodies or dominant negative E-cadherin. In a screen for potential downstream effectors of spheroid cell survival, we detected E-cadherin-dependent activation of the ErbB4 receptor tyrosine kinase but not of other ErbB family members. Reduction of ErbB4 levels by RNA interference blocked Akt activation and spheroid cell survival and restored chemosensitivity to Ewing sarcoma spheroids. Our results indicate that anchorage-independent Ewing sarcoma cells suppress anoikis through a pathway involving E-cadherin cell-cell adhesion, which leads to ErbB4 activation of the phosphatidylinositol 3-kinase-Akt pathway, and that this is associated with increased resistance of cells to cytotoxic agents. [Cancer Res 2007;67(7):3094-105]

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“…In the experiments of Sheng et al (47), FGF-2 was shown to activate the rDNA promoter in a way similar to our demonstration that IRS-1 activates it. Linggi et al (48) found a nuclear fragment of ErbB-4 with an active tyrosine kinase activity. The finding that IRS-1 binds to UBF1 and stimulates rRNA synthesis (13,14) is in itself a strong suggestion of IRS-1 acting as a transcriptional cofactor.…”

Section: Discussionmentioning

confidence: 99%

Insulin Receptor Substrate-1 Regulates the Transformed Phenotype of BT-20 Human Mammary Cancer Cells

Dalmızrak

Chen

et al. 2007

Cancer Research

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Although originating from a human breast cancer, BT-20 cells do not form colonies in soft agar. BT-20 cells do not express insulin receptor substrate-1 (IRS-1), which is known to promote both normal and abnormal growth and to inhibit differentiation. Stable expression of IRS-1 confers to BT-20 cells the ability to form colonies in soft agar. BT-20 cells form tumors in xenografts in mice, but the size of tumors is twice as large when the cells express IRS-1. The increased transformed phenotype is characterized by occupancy of the rDNA and cyclin D1 promoters by IRS-1 and the activation of the cyclin D1, c-myc, and rDNA promoters. In addition, the retinoblastoma protein, which is detectable in the rDNA promoter of quiescent BT-20/IRS-1 cells, is replaced by IRS-1 after insulinlike growth factor-I stimulation. Our results indicate that in BT-20 human mammary cancer cells, expression of IRS-1 activates promoters involved in cell growth and cell proliferation, resulting in a more transformed phenotype. Targeting of IRS-1 could be effective in inhibiting the proliferation of mammary cancer cells. [Cancer Res 2007;67(5):2124-30]

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The ErbB-4 s80 intracellular domain is a constitutively active tyrosine kinase

Cited by 52 publications

References 31 publications

Differential nuclear localization and kinase activity of alternative ErbB4 intracellular domains

Differential nuclear localization and kinase activity of alternative ErbB4 intracellular domains

E-Cadherin Cell-Cell Adhesion in Ewing Tumor Cells Mediates Suppression of Anoikis through Activation of the ErbB4 Tyrosine Kinase

Insulin Receptor Substrate-1 Regulates the Transformed Phenotype of BT-20 Human Mammary Cancer Cells

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