β1A Integrin Expression Is Required for Type 1 Insulin-Like Growth Factor Receptor Mitogenic and Transforming Activities and Localization to Focal Contacts

Abstract

The cells' ability to proliferate in response to growth factor stimulation is significantly altered during cancer progression. To investigate the mechanisms underlying these alterations in prostate cancer, the role and expression of B 1A integrin and type 1 insulin-like growth factor receptor (IGF-IR), known to contribute to cell proliferation and transformation, were analyzed. Using small interfering RNA oligonucleotides to down-regulate B 1A , we show that B 1A expression is required for IGF-IR-mediated prostate cancer cell proliferation and anchorage-independent growth. In vivo, using age-matched transgenic adenocarcinoma of mouse prostate (TRAMP) mice at different stages of prostate cancer [prostatic intraepithelial neoplasia, PIN; well-differentiated adenocarcinoma, WD; and poorly differentiated adenocarcinoma, PD], the expression of B 1A and of IGF-IR was studied. B 1A and IGF-IR expression levels were concurrently up-regulated in high PIN and WD, whereas their expression did not correlate in late-stage PD. In contrast to the up-regulated expression of B 1A , the levels of B 1C , a B 1 cytoplasmic variant that inhibits cell proliferation, were down-regulated in all stages of prostate cancer. A similar expression pattern was observed for a B 1C downstream effector, Grb2-associated binder-1 (Gab1) which is known to inhibit IGF-IR phosphorylation. To analyze in vitro the mechanistic implications of B 1A , B 1C , and Gab1 deregulation in prostate cancer, we investigated whether expression of either B 1 variant in B 1 -null cells affected IGF-IR localization. We found that IGF-IR and B 1A were colocalized in highly specialized integrin signaling compartments, designated focal contacts. However, in the presence of B 1C , IGF-IR remained diffuse on the cell surface and did not localize to focal contacts. The findings that B 1 integrins and IGF-IR are concurrently deregulated and that expression of B 1 integrins is necessary to achieve appropriate IGF-IR intracellular distribution point to the important role that the cross-talk between these receptors may have during prostate cancer progression and will be helpful in formulating new therapeutic strategies. (Cancer Res 2005; 65(15): 6692-700)

Insulin-Like Growth Factor I Controls a Mutually Exclusive Association of RACK1 with Protein Phosphatase 2A and β1 Integrin To Promote Cell Migration

“…Recent studies have suggested that cooperation between IGF-IR and integrin signaling is necessary for the growth and migration of transformed cells (10,18). The data presented here indicate that the scaffolding protein RACK1 plays a central role in integrating this signaling through its interaction with PP2A, which is regulated by IGF-I and ␤1 integrin ligation.…”

“…The characteristics of cells expressing this IGF-IR mutant suggest that integrin signaling is a necessary component of IGF-IR signaling in maintaining the transformed phenotype of these cells. An essential role for ␤1 integrin in IGF-I-mediated tumor growth in prostate cancer was also recently proposed (10).…”

β4 Integrin signaling induces expansion of prostate tumor progenitors

“…Since AR signaling suppresses the expression of β4, c-Met, and ErbB2 (84, 85), androgen withdrawal experiments have suggested that focal adhesion kinase, which is activated by multiple β1 integrins, promotes the expansion of tumor progenitor cells in mouse models of mammary and intestinal tumorigenesis (73)(74)(75). Finally, although not directly focusing on tumor progenitor cells, prior studies have emphasized a role for β1 integrins, but not for β4, in prostate cancer (37,(76)(77)(78)(79). Our observation that β4 signaling is dispensable for prostate development but not tumorigenesis is consistent with the hypothesis that tumor cells are exquisitely dependent on certain integrin signaling pathways, such as those activated by β4, whereas their normal counterpart are not (32,74).…”

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

“…During malignant progression, the complex crosstalk between the IGF axis and integrin signaling contributes to enhanced cell survival, proliferation, migration and invasion (Beattie et al, 2010). Studies by Goel et al (2004Goel et al ( , 2005 have shown that IGF-IR signaling and its mitogenic and transforming activities in prostate cancer cells are regulated by b1 integrin and this involves direct interaction between the two molecules. In addition, crosstalk between the integrin vitronectin receptor avb3 and the IGF-IR has been documented in various tumor cells (Clemmons and Maile, 2003), and the prosurvival effect of fibronectin in pancreatic carcinoma cells was shown to be mediated via IGF-IR and involve the b3 integrin (Edderkaoui et al, 2007).…”