Heregulin Regulates Cytoskeletal Reorganization and Cell Migration through the p21-activated Kinase-1 via Phosphatidylinositol-3 Kinase

Adam, Liana; Vadlamudi, Ratna K.; Kondapaka, Sudhir B.; Chernoff, Jonathan; Mendelsohn, John; Kumar, Rakesh

doi:10.1074/jbc.273.43.28238

Cited by 268 publications

(250 citation statements)

References 35 publications

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“…P21-activated kinase 1 was first demonstrated to be autophosphorylated via directly binding to the Rho GTPases, cdc42 and rac (Adam et al, 1998). Lipids such as sphingosine also activate 3-phosphoinositide-dependent kinase-1, which then directly phosphorylates and activates PAK1 (King et al, 2000).…”

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confidence: 99%

“…Lipids such as sphingosine also activate 3-phosphoinositide-dependent kinase-1, which then directly phosphorylates and activates PAK1 (King et al, 2000). Heregulin also indirectly activates PAK1 via the PI3K/AKT pathway (Adam et al, 1998). Recent data indicate an important role for PAK1 in breast cancer progression.…”

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confidence: 99%

“…Recent data indicate an important role for PAK1 in breast cancer progression. Activation of PAK1 results in actin phosphorylation in breast cancer cells, leading to a reorganisation of the cytoskeleton that favours cell migration and invasiveness (Adam et al, 1998). Activated PAK1 also phosphorylates and activates oestrogen receptor-a (ERa) independently of ligand stimulation, leading to increased Cyclin D1 expression and cell cycle progression (Holm et al, 2006).…”

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Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells

et al. 2008

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The ErbB3 binding protein (Ebp1) is a transcriptional corepressor that inhibits the activity of proliferation-associated genes and the growth of human breast cancer cell lines. Treatment of breast cancer cells with the ErbB3 ligand heregulin (HRG) results in increased phosphorylation of Ebp1 and transcriptional repression. The p21-activated serine/threonine kinase 1 (PAK1), which plays an important role in breast cancer progression and resistance to the anti-oestrogen tamoxifen, is also activated by HRG. We therefore examined the ability of PAK1 to phosphorylate and regulate the function of Ebp1. We found that PAK1 phosphorylated Ebp1 in vitro and mapped the phosphorylation site to threonine 261. Both HRG treatment and expression of a constitutively activated PAK1 in MCF-7 breast cancer cells enhanced threonine phosphorylation of Ebp1. In MCF-7 cells, ectopically expressed Ebp1 bound endogenous PAK1 and this association was enhanced by treatment with HRG. Mutation of the PAK1 phosphorylation site to glutamic acid, mimicking a phosphorylated state, completely abrogated the ability of Ebp1 to repress transcription, inhibit growth of breast cancer cell lines and contribute to tamoxifen sensitivity. These studies demonstrate for the first time that Ebp1 is a substrate of PAK1 and the importance of the PAK1 phosphorylation site for the functional activity of Ebp1 in breast cancer cells.

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Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells

et al. 2008

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“…In addition to HER2 overexpression, accumulating evidence suggests that the HRG pathway may be involved in the progression of breast cancer cells to a more invasive phenotype (Benz et al,. 1993;Kumar et al, 1995;Adam et al, 1998). HRG stimulation of breast cancer cells enhances Shc phosphorylation and its association with phosphorylated HER3 (Kim et al, 1994), activation of PI 3-kinase Adam et al, 1998), and activation of MAP-kinases and JNKkinases (Pinkas-Kramarski et al, 1997;Marte et al, 1995).…”

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“…1993;Kumar et al, 1995;Adam et al, 1998). HRG stimulation of breast cancer cells enhances Shc phosphorylation and its association with phosphorylated HER3 (Kim et al, 1994), activation of PI 3-kinase Adam et al, 1998), and activation of MAP-kinases and JNKkinases (Pinkas-Kramarski et al, 1997;Marte et al, 1995). In spite of the widely acknowledged role of HER2 in breast cancer, the mechanism through which HRG participates in breast cancer progression remains elusive.…”

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Serine phosphorylation of paxillin by heregulin-β1: role of p38 mitogen activated protein kinase

et al. 1999

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The mechanisms through which heregulin (HRG) regulates the progression of breast cancer cells to a more invasive phenotype are currently unknown. Recently we have shown that HRG treatment of breast cancer cells leads to the formation of lamellipodia/ ®lopodia, and increased cell migration and invasiveness through the phosphatidylinositol 3-kinase (PI-3 kinase).Since the process of cell migration must involve changes in adhesion, we explored the potential HRG regulation of paxillin, a major cytoskeletal phosphoprotein of focal adhesion. We report that HRG stimulation of noninvasive breast cancer cells resulted in stimulation of p38 mitogen-activated protein kinase (p38 MAPK ), extracellular signal-regulated kinases (ERK) and PI-3K, and a concurrent unexpected increase in the level of paxillin phosphorylation on serine residue which was sensitive to protein-phosphatase 2b but not to protein tyrosine phosphatase 1. In addition, HRG triggered a rapid redistribution of paxillin to the perinuclear regions from the tyrosine-phosphorylated focal adhesions, and increased cell scattering. There was no e ect of HRG on the state of phosphorylation and localization of focal adhesion kinase. The HRG-induced increase in serine phosphorylation of paxillin and cell scattering were selectively inhibited by a speci®c inhibitor of p38 MAPK or a dominant-negative p38 MAPK mutant, but not by inhibitors of p42/44 MAPK or PI-3 kinase pathways. For the ®rst time our results have shown that HRG, a potent migratory growth factor stimulates serine phosphorylation of paxillin. These ®ndings suggest a role of p38 MAPKdependent signal transduction pathway(s) in serine phosphorylation and disassembly of the paxillin from the focal complexes during HRG-induced cell shape alterations and motility.

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Role of HER2 gene overexpression in breast carcinoma

et al. 2000

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The HER2 proto-oncogene encodes a transmembrane glycoprotein of 185 kDa (p185(HER2)) with intrinsic tyrosine kinase activity. Amplification of the HER2 gene and overexpression of its product induce cell transformation. Numerous studies have demonstrated the prognostic relevance of p185(HER2), which is overexpressed in 10% to 40% of human breast tumors. Recent data suggest that p185(HER2) is a ligand orphan receptor that amplifies the signal provided by other receptors of the HER family by heterodimerizing with them. Ligand-dependent activation of HER1, HER3, and HER4 by EGF or heregulin results in heterodimerization and, thereby, HER2 activation. HER2 overexpression is associated with breast cancer patient responsiveness to doxorubicin, to cyclophosphamide, methotrexate, and fluorouracil (CMF), and to paclitaxel, whereas tamoxifen was found to be ineffective and even detrimental in patients with HER2-positive tumors. In vitro analyses have shown that the role of HER2 overexpression in determining the sensitivity of cancer cells to drugs is complex, and molecules involved in its signaling pathway are probably the actual protagonists of the sensitivity to drugs. The association of HER2 overexpression with human tumors, its extracellular accessibility, as well as its involvement in tumor aggressiveness are all factors that make this receptor an appropriate target for tumor-specific therapies. A number of approaches are being investigated as possible therapeutic strategies that target HER2: (1) growth inhibitory antibodies, which can be used alone or in combination with standard chemotherapeutics; (2) tyrosine kinase inhibitors (TKI), which have been developed in an effort to block receptor activity because phosphorylation is the key event leading to activation and initiation of the signaling pathway; and (3) active immunotherapy, because the HER2 oncoprotein is immunogenic in some breast carcinoma patients.

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Heregulin Regulates Cytoskeletal Reorganization and Cell Migration through the p21-activated Kinase-1 via Phosphatidylinositol-3 Kinase

Cited by 268 publications

References 35 publications

Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells

Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells

Serine phosphorylation of paxillin by heregulin-β1: role of p38 mitogen activated protein kinase

Role of HER2 gene overexpression in breast carcinoma

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