Splice variants of human b1 integrins: origin, biosynthesis and functions

Armulik, Annika

doi:10.2741/armulik

Cited by 9 publications

(4 citation statements)

References 36 publications

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“…Integrin signaling is facilitated through respective types of splice variants expressed (Sakai et al, 1998;Armulik, 2002). Two splice variants in the b1-integrin cytoplasmic domains, b1A and b1D, display two conserved NPxY motifs.…”

Section: Introductionmentioning

confidence: 99%

β1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury

et al. 2005

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Integrin-mediated adhesion to extracellular matrix proteins confers resistance to radiation-or drug-induced genotoxic injury. To analyse the underlying mechanisms specific for b1-integrins, wild-type b1A-integrin-expressing GD25b1A cells were compared to GD25b1B cells, which express signaling-incompetent b1B variants. Cells grown on fibronectin, collagen-III, b1-integrin-IgG or poly-l-lysine were exposed to 0-6 Gy X-rays in presence or depletion of growth factors and phosphatidylinositol-3 kinase (PI3K) inhibitors (LY294002, wortmannin). In order to test the relevance of these findings in tumor cells, human A-172 glioma cells were examined under the same conditions after siRNA-mediated silencing of b1-integrins. We found that b1A-integrin-mediated adhesion to fibronectin, collagen-III or b1-IgG was essential for cell survival after radiation-induced genotoxic injury. Mediated by PI3K, pro-survival b1A-integrin/Akt signaling was critically involved in this process. Additionally, the b1-integrin downstream targets p130Cas and paxillinimpaired survival-regulating PI3K-dependent JNK. In A-172 glioma cells, b1-integrin knockdown and PI3K inhibition confirmed the central role of b1-integrins in Akt-and p130Cas/paxillin-mediated prosurvival signaling. These findings suggest b1-integrins as critical regulators of cell survival after radiation-induced genotoxic injury. Elucidation of the molecular circuitry of prosurvival b1-integrin-mediated signaling in tumor cells may promote the development of innovative moleculartargeted therapeutic antitumor strategies.

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Section: Introductionmentioning

confidence: 99%

β1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury

et al. 2005

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“…Members of the largest subfamily of integrins share β1 as the common β‐subunit. The cytoplasmic domains of β1A and β1D splice variants (Armulik, 2002) each contain two conserved NPXY motifs. These motifs are utilized for several interactions, and their involvement in the inside‐out activation of integrins (Pfaff et al , 1998; Calderwood & Ginsberg, 2003; Tadokoro et al , 2003) as well as in the regulation of FAK activation (Wennerberg et al , 2000) has been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

“…Integrins containing the β1B splice form, which lacks the carboxy‐terminal half of β1A including the NPXY motifs, are in an inactive conformation and cannot bind the normal β1‐integrin ligands. The β1B variant has no apparent physiologic function and probably arises through a splicing error (Armulik, 2002). Such integrins can, however, mediate cell adhesion to anti‐integrin IgG and the bacterial protein invasin without inducing FAK activation (Armulik et al , 2000; Gustavsson et al , 2002).…”

Section: Introductionmentioning

confidence: 99%

β1‐Integrins induce phosphorylation of Akt on serine 473 independently of focal adhesion kinase and Src family kinases

et al. 2004

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Adhesion by means of b1-integrins induces the phosphorylation of Akt, an event strictly dependent on the activity of the phosphatidylinositol 3-kinase (PI3K). Binding of the p85 regulatory subunit of PI3K to phosphorylated tyrosine 397 in focal adhesion kinase (FAK) is considered to be the mechanism of cell adhesion-induced activation of class Ia PI3K. Here we show that PI3K-dependent phosphorylation of Akt in response to ligation of b1-integrins occurs efficiently in the absence of FAK tyrosine phosphorylation. Akt S473 phosphorylation was strongly promoted both in cells expressing the integrin subunit splice variant b1B, which is unable to activate FAK, and in FAK knockout cells. In addition, we found this phosphorylation to be independent of the Src family kinases Src, Fyn and Yes. These results indicate that a major pathway for adhesion-dependent activation of PI3K/Akt is triggered by the membrane proximal part of the b1 subunit in a FAK and Src-independent manner.

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“…Alternative splicing of mRNA from several integrin subunit genes is known to produce different proteins [20][21][22][23][24][25][26][27]. To be inclusive of all the integrin messages, we intentionally selected exons that were not alternatively spliced in the above-mentioned expression study using the four sets of primers (I-IV).…”

Section: Detection Of Differential Splicing Of Selected Integrin Genementioning

confidence: 99%

Gene expression analysis of an integrin family of genes by systematic multiplex reverse transcription‐polymerase chain reaction

Yamamoto¹,

Yamamoto²,

Leung³

et al. 2004

Electrophoresis

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We have established the systematic multiplex reverse transcription-polymerase chain reaction (SM RT-PCR) system of 26 members of the integrin family of genes, and used this system to investigate their expression in 25 different kinds of human adult tissues. A hierarchical clustering analysis of the tissue expression data illustrated clustering of functionally related tissues. Although the correlation was weak, bone marrow, thymus, and spleen were clustered, potentially confirming the role of certain integrin molecules in the immune response. We also investigated changes in integrin gene expression in cancer. Several differences were observed between normal and tumor, as well as between normal and cancer cell lines. The SM RT-PCR experiments for the study of alternative splicing showed that most of the integrin genes analyzed exhibited fixed ratios of differentially spliced transcripts probably due to a tissue-independent mechanism of splicing predetermined by the nucleotide sequences around the splicing donor and acceptor sites.

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Splice variants of human b1 integrins: origin, biosynthesis and functions

Cited by 9 publications

References 36 publications

β1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury

β1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury

β1‐Integrins induce phosphorylation of Akt on serine 473 independently of focal adhesion kinase and Src family kinases

Gene expression analysis of an integrin family of genes by systematic multiplex reverse transcription‐polymerase chain reaction

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