SRC-3Δ4 Mediates the Interaction of EGFR with FAK to Promote Cell Migration

Long, Weiwen; Yi, Ping; Amazit, Larbi; LaMarca, Heather L.; Ashcroft, Felicity; Kumar, Rakesh; Mancini, Michael A.; Tsai, Sophia Y.; Tsai, Ming‐Jer; O’Malley, Bert W.

doi:10.1016/j.molcel.2010.01.004

Cited by 128 publications

(122 citation statements)

References 36 publications

(53 reference statements)

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“…FAK Tyr194 phosphorylation by c-Met appears to interfere with the inhibitory intramolecular interaction leading to its activation (Chen et al, 2011). The FAK FERM domain also binds EGF receptor, promoting migration via mediation of the intermediary protein SRC3D4 after EGF treatment (Long et al, 2010). These previous studies support growth factor (but not adhesion) -mediated FAK activation though interactions of the FERM domain and growth factor receptors.…”

Section: Discussionmentioning

confidence: 68%

Tetraspan TM4SF5-dependent direct activation of FAK and metastatic potential of hepatocarcinoma cells

Jung¹,

Choi²,

Jang

et al. 2012

Journal of Cell Science

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SummaryTransmembrane 4 L six family member 5 (TM4SF5) plays an important role in cell migration, and focal adhesion kinase (FAK) activity is essential for homeostatic and pathological migration of adherent cells. However, it is unclear how TM4SF5 signaling mediates the activation of cellular migration machinery, and how FAK is activated during cell adhesion. Here, we showed that direct and adhesiondependent binding of TM4SF5 to FAK causes a structural alteration that may release the inhibitory intramolecular interaction in FAK. In turn, this may activate FAK at the cell's leading edge, to promote migration/invasion and in vivo metastasis. TM4SF5-mediated FAK activation occurred during integrin-mediated cell adhesion. TM4SF5 was localized at the leading edge of the cells, together with FAK and actin-organizing molecules, indicating a signaling link between TM4SF5/FAK and actin reorganization machinery. Impaired interactions between TM4SF5 and FAK resulted in an attenuated FAK phosphorylation (the signaling link to actin organization machinery) and the metastatic potential. Our findings demonstrate that TM4SF5 directly binds to and activates FAK in an adhesiondependent manner, to regulate cell migration and invasion, suggesting that TM4SF5 is a promising target in the treatment of metastatic cancer.

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Section: Discussionmentioning

confidence: 68%

Tetraspan TM4SF5-dependent direct activation of FAK and metastatic potential of hepatocarcinoma cells

Jung¹,

Choi²,

Jang

et al. 2012

Journal of Cell Science

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“…This increase in transcription is most likely due to a relief of repression of the endogenous AIB1 in the COS-7 cells because we are able to detect endogenous AIB1 protein by Western blot (17). Previous studies from our group and others have suggested that the N-terminal region containing the bHLH and PAS A domains contains an inhibitory domain that represses activity in both the nucleus and cytoplasm (17,18,21,26,36). Our studies and those from Chen et al (36) have shown that the loss of the N-terminal region leads to potent coactivation of nuclear hormone receptor-mediated transcription.…”

Section: Discussionmentioning

confidence: 74%

“…These data suggest a suppressor role of the N-terminal region of AIB1 in the regulation of the coactivator function of AIB1. This region is the most highly conserved region among steroid receptor coactivator proteins and has been suggested to contain an inhibitory function for AIB1 also in the cytoplasm (21).…”

Section: Journal Of Biological Chemistry 26821mentioning

confidence: 99%

Role of the Nuclear Receptor Coactivator AIB1-Δ4 Splice Variant in the Control of Gene Transcription

Chien

Kirilyuk

et al. 2011

Journal of Biological Chemistry

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The oncogene amplified in breast cancer 1 (AIB1) is a nuclear receptor coactivator that plays a major role in the progression of various cancers. We previously identified a splice variant of AIB1 called AIB1-⌬4 that is overexpressed in breast cancer. Using mass spectrometry, we define the translation initiation of AIB1-⌬4 at Met 224 of the full-length AIB1 sequence and have raised an antibody to a peptide representing the acetylated N terminus. We show that AIB1-⌬4 is predominantly localized in the cytoplasm, although leptomycin B nuclear export inhibition demonstrates that AIB1-⌬4 can enter and traffic through the nucleus. Our data indicate an import mechanism enhanced by other coactivators such as p300/CBP. We report that the endogenously and exogenously expressed AIB1-⌬4 is recruited as efficiently as full-length AIB1 to estrogen-response elements of genes, and it enhances estrogen-dependent transcription more effectively than AIB1. Expression of an N-terminal AIB1 protein fragment, which is lost in the AIB1-⌬4 isoform, potentiates AIB1 as a coactivator. This suggests a model whereby the transcriptional activity of AIB1 is squelched by a repressive mechanism utilizing the N-terminal domain and that the increased coactivator function of AIB1-⌬4 is due to the loss of this inhibitory domain. Finally, we show, using Scorpion primer technology, that AIB1-⌬4 expression is correlated with metastatic capability of human cancer cell lines.Gene transcription in eukaryotes is a complex and highly regulated process. One of the major controls of gene transcription is exerted by the coregulator family of proteins. These include both corepressors, which dampen transcription, and coactivators, which potentiate transcription. A subgroup of coactivators has been shown to be critical for the malignant progression of cancer and is known as the p160 steroid receptor coactivators (1). One member in particular was identified to be amplified in breast cancer. Amplified in breast cancer 1 (AIB1, SRC-3, NCOA3, ACTR, TRAM-1, pCIP, and RAC3) has been shown to be a gene amplified in breast cancer (2) and is also overexpressed at the mRNA and protein level in various cancers (1, 3, 4). Its role in tumorigenesis is attributed to its ability to coactivate both steroid hormone-and growth factor-dependent transcription (3, 5-7). In several oncogene-driven mouse models (8 -11), reduction of AIB1 levels leads to a decrease in tumorigenesis, and overexpression of AIB1 leads to the formation of various tumors (12). Clinically, AIB1 expression in breast cancer cases is correlated with high HER2 levels, larger tumor size, higher tumor grade, and shorter disease-free survival (13-15). Also, high levels of AIB1 in conjunction with high HER2 levels coincide with reduced disease-free survival in patients treated with tamoxifen, suggesting a role for AIB1 in tamoxifen resistance (16).We had previously identified a splice variant of AIB1, where exon 3 was spliced from the mature mRNA and the resulting protein named AIB1-⌬3 (17). More recently, an additio...

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“…4C). c-Src is a tyrosine kinase which is involved in the phosphorylation and activation of FAK [35]. By means of western blotting analysis we demonstrated that in MDA-MB231 cells SAHA and TRAIL neither alone nor in combination modified the level of c-Src (not shown).…”

Section: The Effects Of Saha and Trail On The Level Of Integrins And Fakmentioning

confidence: 89%

SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells

et al. 2012

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a b s t r a c t SAHA, an inhibitor of histone deacetylase activity, has been shown to sensitize tumor cells to apoptosis induced by TRAIL, a member of TNF-family. In this paper we investigated the effect of SAHA/TRAIL combination in two breast cancer cell lines, the ERaÀpositive MCF-7 and the ERaÀnegative MDA-MB231. Treatment of MDA-MB231 and MCF-7 cells with SAHA in combination with TRAIL caused detachment of cells followed by anoikis, a form of apoptosis which occurs after cell detachment, while treatment with SAHA or TRAIL alone did not produce these effects. The effects were more evident in MDA-MB231 cells, which were chosen for ascertaining the mechanism of SAHA/TRAIL action. Our results show that SAHA decreased the level of c-FLIP, thus favouring the interaction of TRAIL with the specific death receptors DR4 and DR5 and the consequent activation of caspase-8. These effects increased when the cells were treated with SAHA/TRAIL combination. Because z-IEDT-fmk, an inhibitor of caspase-8, prevented both the cleavage of the focal adhesion-kinase FAK and cell detachment, we suggest that activation of caspase-8 can be responsible for both the decrement of FAK and the consequent cell detachment. In addition, treatment with SAHA/TRAIL combination caused dissipation of DJ m , activation of caspase-3 and decrement of both phospho-EGFR and phospho-ERK1/2, a kinase which is involved in the phosphorylation of BimEL. Therefore, co-treatment also induced decrement of phospho-BimEL and a concomitant increase in the dephosphorylated form of BimEL, which plays an important role in the induction of anoikis.Our findings suggest the potential application of SAHA in combination with TRAIL in clinical trials for breast cancer.

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SRC-3Δ4 Mediates the Interaction of EGFR with FAK to Promote Cell Migration

Cited by 128 publications

References 36 publications

Tetraspan TM4SF5-dependent direct activation of FAK and metastatic potential of hepatocarcinoma cells

Tetraspan TM4SF5-dependent direct activation of FAK and metastatic potential of hepatocarcinoma cells

Role of the Nuclear Receptor Coactivator AIB1-Δ4 Splice Variant in the Control of Gene Transcription

SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells

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