α6β1 integrin induces proteasome-mediated cleavage of erbB2 in breast cancer cells

Shimizu, Hajime; Seiki, Takashi; Asada, Makoto; Yoshimatsu, Kentaro; Koyama, Noriyuki

doi:10.1038/sj.onc.1206203

Cited by 16 publications

(14 citation statements)

References 55 publications

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Section: Introductionmentioning

confidence: 93%

“…HSP90 inhibition also induces cleavage of the cytoplasmic part of ErbB2, resulting in a transmembrane 135-kDa ErbB2 and short-lived cytoplasmic fragments (Tikhomirov and Carpenter, 2000;Lerdrup et al, 2006). The cleavage occurs in the kinase domain and a similar cleavage is seen after stimulation with curcumin or staurosporine (Tikhomirov and Carpenter, 2001) or in cells with high levels of ␣6␤1 integrin (Shimizu et al, 2003).It has remained elusive whether endocytosis and C-terminal cleavage of ErbB2 are independent or correlated events. If positively correlated, C-terminal cleavage of ErbB2 could promote endocytosis by releasing ErbB2 from a retention mechanism that normally sequesters the receptor at the plasma membrane (Sorkin et al, 1993;Hommelgaard et al, 2004;Lerdrup et al, 2006) or by exposure of an unknown cryptic motif stimulating endocytosis.…”

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confidence: 99%

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Endocytic Down-Regulation of ErbB2 Is Stimulated by Cleavage of Its C-Terminus

Lerdrup

Bruun

Grandal

et al. 2007

MBoC

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High ErbB2 levels are associated with cancer, and impaired endocytosis of ErbB2 could contribute to its overexpression. Therefore, knowledge about the mechanisms underlying endocytic down-regulation of ErbB2 is warranted. The Cterminus of ErbB2 can be cleaved after various stimuli, and after inhibition of HSP90 with geldanamycin this cleavage is accompanied by proteasome-dependent endocytosis of ErbB2. However, it is unknown whether C-terminal cleavage is linked to endocytosis. To study ErbB2 cleavage and endocytic trafficking, we fused yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP) to the N-and C-terminus of ErbB2, respectively (YFP-ErbB2-CFP). After geldanamycin stimulation YFP-ErbB2-CFP became cleaved in nonapoptotic cells in a proteasome-dependent manner, and a markedly larger relative amount of cleaved YFP-ErbB2-CFP was observed in early endosomes than in the plasma membrane. Furthermore, cleavage took place at the plasma membrane, and cleaved ErbB2 was internalized and degraded far more efficiently than full-length ErbB2. Concordantly, a C-terminally truncated ErbB2 was also readily endocytosed and degraded in lysosomes compared with full-length ErbB2. Altogether, we suggest that geldanamycin leads to C-terminal cleavage of ErbB2, which releases the receptor from a retention mechanism and causes endocytosis and lysosomal degradation of ErbB2. INTRODUCTIONThe receptor tyrosine kinase ErbB2 is a potent oncoprotein, and a high ErbB2 level can by itself activate ErbB receptors (Worthylake et al., 1999). Concordantly, increased ErbB2 levels can be found in several cancers (Klapper et al., 2000;Yarden, 2001), and high ErbB2 levels are correlated to a worse prognosis for breast cancer patients (Slamon et al., 1987;Hynes and Stern, 1994;De Placido et al., 1998;Pegram et al., 1998). Gene amplification is the most studied mechanisms causing high ErbB2 levels, but also posttranscriptional regulation of ErbB2 plays a role in cancers (Vernimmen et al., 2003;Magnifico et al., 2007). Little attention has been paid to the role of ErbB2 degradation in cancers, although when compromised it also would lead to increased ErbB2 levels and activity. Several studies have shown that endocytic downregulation of ErbB2 is impaired in cancer cells (Sorkin et al., 1993; Baulida et al., 1996;Wang et al., 1999;Hommelgaard et al., 2004;Austin et al., 2004;Longva et al., 2005), and ErbB2 can even transmit this property to the related epidermal growth factor receptor (EGFR; Muthuswamy et al., 1999;Wang et al., 1999;Worthylake et al., 1999;Haslekas et al., 2005). Inhibition of HSP90 (e.g., with geldanamycin [GA]) leads to increased internalization and lysosomal degradation of ErbB2 in a manner depending on proteasomal activity (Tikhomirov and Carpenter, 2000;Austin et al., 2004;Lerdrup et al., 2006). HSP90 inhibition also induces cleavage of the cytoplasmic part of ErbB2, resulting in a transmembrane 135-kDa ErbB2 and short-lived cytoplasmic fragments (Tikhomirov and Carpenter, 2000;Lerdrup et al., 2006). The cleavage oc...

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Section: Introductionmentioning

confidence: 93%

mentioning

confidence: 99%

Endocytic Down-Regulation of ErbB2 Is Stimulated by Cleavage of Its C-Terminus

Lerdrup

Bruun

Grandal

et al. 2007

MBoC

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“…Increasing evidence suggests an interplay between HER-2 and integrins (19,20), a large family of cell surface heterodimeric receptors composed of α and β subunits (21). The β 1 subunit, which is encoded by the ITGB1 gene (also known as CD29 and VLAB), plays a major role in mediating cell-ECM interactions (22) and druginduced (23)(24)(25) or radiation-induced resistance (26), as well as in tumor initiation (27), progression, and invasion (22).…”

Section: Introductionmentioning

confidence: 99%

“…In this regard, increased expression of β 1 -integrin was associated with poor prognosis in patients with small-cell lung cancer (28), melanoma (29), and invasive breast cancer (30). Several arguments support the tenet that the deleterious effects of increased β 1 -integrin expression merit further investigation in the context of HER-2-positive breast cancer, notably, (a) binding of β 1 -integrin to ECM induces similar downstream signaling pathways to HER-2 (31), such as the PI3K/ Akt and extracellular signal-regulated kinase1/2 (ERK1/2) pathways (32); (b) reciprocal interactions (i.e., cross-talk) between HER-2 and integrins were reported in different cell types (19,20); (c) β 1 -integrin is overexpressed in JIMT-1 (33), a HER-2-positive breast cancer cell line isolated from a patient who did not respond to trastuzumab (34). Nonetheless, the prognostic relevance of β 1 -integrin expression in HER-2-positive breast cancer specimens and the functional consequences of its level of expression have not been investigated with respect to trastuzumab response.…”

Section: Introductionmentioning

confidence: 99%

β1-Integrin Circumvents the Antiproliferative Effects of Trastuzumab in Human Epidermal Growth Factor Receptor-2–Positive Breast Cancer

Lesniak

Deschênes

et al. 2009

Cancer Research

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Resistance to trastuzumab, the monoclonal antibody targeting human epidermal growth factor receptor 2 (HER-2), is a major concern for HER-2-positive metastatic breast cancer (MBC) patients. To date, HER-2 status is the only available biomarker for selecting patients for trastuzumab-based therapy. β 1 -Integrin, an adhesion molecule involved in cell survival and drug resistance, shares common downstream signaling elements with HER-2, such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase-1/2 (ERK1/2) pathways. The significance of β 1 -integrin expression in HER-2-positive breast cancer and its involvement in a patient's response to trastuzumab-based therapy are unknown. We show here that overexpression of β 1 -integrin is an independent negative prognostic factor for tumor progression of HER-2-positive MBC patients treated with trastuzumab-based chemotherapy. Enforced overexpression of β 1 -integrin, its small interfering RNA-induced knockdown or treatment with a β 1 -integrin-blocking antibody in HER-2-positive breast cancer cells, identified a strong inverse relationship between expression level of β 1 -integrin and in vitro sensitivity to trastuzumab. Notably, β 1 -integrin overexpression increased the phosphorylation of Akt-Ser473 and ERK1/2, thereby promoting survival and mitogenic signals to bypass the antiproliferative effects of trastuzumab. Our findings show that β 1 -integrin provides a novel independent prognostic biomarker of trastuzumab response in HER-2-positive MBC patients and suggest a new target to augment the antiproliferative effects of trastuzumab. [Cancer Res 2009;69(22):8620-8]

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“…However, evidence supporting this explanation has yet to be reported. On the other hand, a recent study in breast cancer cells showed that 61 integrin inhibits HER2 signals by inducing proteasome-dependent proteolytic cleavage of the HER2 cytoplasmic domain [46]. Since the antibody that we used labels the cytoplasmic domain of the HER2 molecule, this proteolytic cleavage may cause a low immunoreaction for HER2 in the basal layer.…”

Section: Discussionmentioning

confidence: 84%