Beta 1 integrin function in vivo: Adhesion, migration and more

Max Planck Institute of Biochemistry, Junior Group Regulation of Cytoskeletal Organization, Martinsried, Germany.
Cancer and metastasis reviews (Impact Factor: 7.23). 10/2005; 24(3):403-11. DOI: 10.1007/s10555-005-5132-5
Source: PubMed

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    • "Lys-38 of the Tβ4 protein is cross-linked to Gln-41, a G-actin monomer leading to the formation of 1∶1 complexes [3]. Tβ4 can also depolymerize F-actin resulting in multiple diverse cellular functions [4]. Tβ4 plays a role in anti-apoptotic response to an external stress [5], paclitaxel-resistance via ROS production [6]–[8] and HIF-1α stabilization via Erk activation [9]. "
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    ABSTRACT: The actin-sequestering protein thymosin beta-4 (Tβ4) is involved in various cellular and physiological processes such as proliferation, motility, growth and metastasis. Nitric oxide (NO) promotes tumor invasiveness and metastasis by activating various enzymes. Herein, we investigated whether hypoxia-inducible NO regulates Tβ4 expression and cancer cell migration using HeLa cervical cancer cells. NO production and Tβ4 expression were increased in a hypoxic condition. The treatment with N-(β-D-Glucopyranosyl)-N2-acetyl-S-nitroso-D, L-penicillaminamide (SNAP-1), to generate NO, enhanced the transcription of Tβ4 and cancer cell migration. SNAP-1-induced cell migration was decreased by the inhibition of Tβ4 with small interference (si) RNA. In a hypoxic condition, treatment with NG-monomethyl-L-arginine (L-NMMA), nitric oxide synthase (NOS) inhibitor, reduced Tβ4 transcriptional activity, and hypoxia-inducible factor (HIF)-1α. Hypoxia-induced cancer cell migration was also decreased by L-NMMA treatment. In a normoxic condition, Tβ4 transcriptional activity was decreased in the cells incubated in the presence of L-NMMA after co-transfection with Tβ4 promoter and GST-conjugated HIF-1α. Collectively, these results suggest that NO could regulate the expression of Tβ4 by direct or indirect effect of HIF-1α on Tβ4 promoter.
    Full-text · Article · Oct 2014 · PLoS ONE
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    • "While involvement of integrins in adhesion and migration are obvious, recent work illustrates a regulatory function of integrins in survival and therapy resistance of malignant tumors. Owing to their frequent overexpression in different tumor entities [31–33,63–67] and their dual functionality in structure and signaling [12] [22] [24], integrins emerged as potential cancer targets . In contrast to cytoplasmic kinases, therapeutic approaches can leverage the transmembrane localization of integrins and receptor tyrosine kinase for antibody-mediated targeting or molecular imaging as demonstrated with peptidomimetic Cilengitide binding to ␣v␤3 and ␣v␤5 integrins [68] [69] [70] [71] [72]. "
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    ABSTRACT: Interlocking gene mutations, epigenetic alterations and microenvironmental features perpetuate tumor development, growth, infiltration and spread. Consequently, intrinsic and acquired therapy resistance arises and presents one of the major goals to solve in oncologic research today. Among the myriad of microenvironmental factors impacting on cancer cell resistance, cell adhesion to the extracellular matrix (ECM) has recently been identified as key determinant. Despite the differentiation between cell adhesion-mediated drug resistance (CAMDR) and cell adhesion-mediated radioresistance (CAMRR), the underlying mechanisms share great overlap in integrin and focal adhesion hub signaling and differ further downstream in the complexity of signaling networks between tumor entities. Intriguingly, cell adhesion to ECM is per se also essential for cancer cells similar to their normal counterparts. However, based on the overexpression of focal adhesion hub signaling receptors and proteins and a distinct addiction to particular integrin receptors, targeting of focal adhesion proteins has been shown to potently sensitize cancer cells to different treatment regimes including radiotherapy, chemotherapy and novel molecular therapeutics. In this review, we will give insight into the role of integrins in carcinogenesis, tumor progression and metastasis. Additionally, literature and data about the function of focal adhesion molecules including integrins, integrin-associated proteins and growth factor receptors in tumor cell resistance to radio- and chemotherapy will be elucidated and discussed.
    Full-text · Article · Aug 2014 · Seminars in Cancer Biology
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    • "β1-integrin signals through a variety of different mechanisms including but not limited to associating with other membrane proteins, serving as a binding dock for intracellular signaling molecules to bind and aggregate, and activating a specific set of intracellular domain bound kinases such as focal adhesion kinase (FAK) and integrin-linked kinase (ILK) [1], [5]. Integrin-linked kinase (ILK) is a 59kDa serine/threonine protein kinase that associates with the cytoplasmic domain of β-integrins and transduces signaling after activation of the integrin [17]. "
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    ABSTRACT: Astrogliosis with glial scar formation after damage to the nervous system is a major impediment to axonal regeneration and functional recovery. The present study examined the role of β1-integrin signaling in regulating astrocytic differentiation of neural stem cells. In the adult spinal cord β1-integrin is expressed predominantly in the ependymal region where ependymal stem cells (ESCs) reside. β1-integrin signaling suppressed astrocytic differentiation of both cultured ESCs and subventricular zone (SVZ) progenitor cells. Conditional knockout of β1-integrin enhanced astrogliogenesis both by cultured ESCs and by SVZ progenitor cells. Previous studies have shown that injection into the injured spinal cord of a self-assembling peptide amphiphile that displays an IKVAV epitope (IKVAV-PA) limits glial scar formation and enhances functional recovery. Here we find that injection of IKVAV-PA induced high levels of β1-integrin in ESCs in vivo, and that conditional knockout of β1-integrin abolished the astroglial suppressive effects of IKVAV-PA in vitro. Injection into an injured spinal cord of PAs expressing two other epitopes known to interact with β1-integrin, a Tenascin C epitope and the fibronectin epitope RGD, improved functional recovery comparable to the effects of IKVAV-PA. Finally we found that the effects of β1-integrin signaling on astrogliosis are mediated by integrin linked kinase (ILK). These observations demonstrate an important role for β1-integrin/ILK signaling in regulating astrogliosis from ESCs and suggest ILK as a potential target for limiting glial scar formation after nervous system injury.
    Full-text · Article · Aug 2014 · PLoS ONE
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