Structural Basis of Binding by Cyclic Nonphosphorylated Peptide Antagonists of Grb7 Implicated in Breast Cancer Progression

Ambaye, Nigus D.; Pero, Stephanie C.; Gunzburg, Menachem J.; Yap, MinYin; Clayton, Daniel; Borgo, Mark P. Del; Perlmutter, Patrick; Aguilar, Marie‐Isabel; Shukla, Girja S.; Peletskaya, Elena N.; Cookson, Michelle; Krag, David N.; Wilce, Matthew Charles James; Wilce, Jacqueline Anne

doi:10.1016/j.jmb.2011.07.030

Cited by 21 publications

(48 citation statements)

References 49 publications

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“…We and others have previously reported that GRB7 is frequently overexpressed and promotes cell proliferation, cell migration and cell invasion of human cancers [10], [12], [42]. Given to its important roles as signal transduction molecules in activating oncogenic signaling pathways, numerous studies have attempted to develop inhibitors targeting to the SH2 domain of GRB7 in order to inhibiting aberrant activation of related signaling activities and eliminating cancer cells [43], [44], [45], [46]. For examples, the combination of Grb7 cyclic peptide, G7-18NATE, with chemo-drugs were capable of inhibiting breast cancer cell growth [47], [48], or with the specific peptide ligand to suppress GRB7-mediated metastasis in pancreatic carcinoma etc [11], [49].…”

Section: Discussionmentioning

confidence: 99%

Targeting GRB7/ERK/FOXM1 Signaling Pathway Impairs Aggressiveness of Ovarian Cancer Cells

et al. 2012

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Ovarian cancer is a highly lethal disease with poor prognosis and especially in high-grade tumor. Emerging evidence has reported that aberrant upregulation and activation of GRB7, ERK as well as FOXM1 are closely associated with aggresivenesss of human cancers. However, the interplay between these factors in the pathogenesis of human cancers still remains unclear. In this study, we found that GRB7 (P<0.0001), ERK phosphorylation (P<0.0001) and FOXM1 (P = 0.001) were frequently increased and associated with high-grade tumors, as well as a high tendency in association with advanced stage ovarian cancer by immunohistochemical analysis. Intriguingly, the expressions of GRB7 (P<0.0001), ERK phosphorylation (P<0.001) and FOXM1 (P<0.001) showed a significant stepwise increase pattern along Grade 1 to Grade 3 ovarian cancers. Biochemical studies using western blot analysis demonstrated that enforced expression or knockdown of GRB7 showed GRB7 could elevate the levels of ERK phosphorylation and FOXM1, whereas enforced expression of FOXM1 could not alter levels of GRB7 and ERK phosphorylation. But inhibition of ERK signaling by U0126 or PD98059 could reduce the level of FOXM1 in GRB7-overexpressing ovarian cancer cells, suggesting that GRB7, ERK and FOXM1 are regulated orderly. Moreover, inhibition of ERK activity by U0126 or PD98059, or decreased FOXM1 expression by Thiostrepton significantly inhibited cell migration/invasion, tumor growth in vitro and in vivo. Collectively, our findings confer that targeting GRB7/ERK/FOXM1 signaling cascade may be a promising molecular therapeutic choice in combating ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Targeting GRB7/ERK/FOXM1 Signaling Pathway Impairs Aggressiveness of Ovarian Cancer Cells

et al. 2012

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“…In contrast, the EF loop assumes a “bent” conformation in both the unliganded and the inhibitor-bound crystal structures (2QMS and 3PQZ), corresponding with substantially greater surface exposure of hydrophobic sidechains in the pY+3 binding pocket region ((Fig. 3A ), showing the unliganded structure only; note its close conformational similarity with the inhibitor-bound structure [8]). The existence of two EF loop conformations (extended and bent) in the Grb7-SH2 domain is supported by prior backbone nuclear relaxation measurements, which point to increased mobility in the EF loop region [10].…”

Section: Resultsmentioning

confidence: 99%

“…Our group published a solution structure of the Grb7-SH2 domain in complex with pY1139, a phosphorylated ten-amino-acid peptide representative of the activated erbB2 receptor [5]. More recent crystallographic studies have produced structures of the Grb7-SH2 domain alone [7] and in complex with a nonphosphorylated inhibitor [8]. Although in vitro analyses indicate that the ligand-bound Grb7-SH2 domain is predominantly monomeric [7, 9–10], the NMR complex remains the only experimentally determined structure of a monomeric Grb7-SH2 domain with a bound ligand.…”

Section: Introductionmentioning

confidence: 99%

Water-Refined Solution Structure of the Human Grb7-SH2 Domain in Complex with the erbB2 Receptor Peptide pY1139

Pias¹,

Johnson²,

Smith³

et al. 2012

PPL

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We report a refinement in implicit water of the previously published solution structure of the Grb7-SH2 domain bound to the erbB2 receptor peptide pY1139. Structure quality measures indicate substantial improvement, with residues in the most favored regions of the Ramachandran plot increasing by 14 % and with WHAT IF statistics (Vriend, G. J. Mol. Graph. , 19908 (1), 52–56) falling closer to expected values for well-refined structures.

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“…The same research group recently reported a second generation bicyclic peptide inhibitor derived from G7–18NATE with improved binding affinity for the SH2 domain of Grb7 [51]. The crystal structure of a G7–18NATE–Grb7-SH2 domain complex showed that Trp 1 and Thr 8 of the lead were not directly involved in binding interactions [52]. Based on this observation, Wilce and coworkers explored the hypothesis that constricting the inhibitor in its bound conformation would result in an improved affinity for the Grb7-SH2 domain.…”

Section: Inhibitors Targeting Grb7mentioning

confidence: 99%

Targeting Sh2 Domains in Breast Cancer

et al. 2014

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Breast cancer is among the most commonly diagnosed cancer types in women worldwide and is the second leading cause of cancer-related disease in the USA. SH2 domains recruit signaling proteins to phosphotyrosine residues on aberrantly activated growth factor and cytokine receptors and contribute to cancer cell cycling, metastasis, angiogenesis and so on. Herein we review phosphopeptide mimetic and small-molecule approaches targeting the SH2 domains of Grb2, Grb7 and STAT3 that inhibit their targets and reduce proliferation in in vitro breast cancer models. Only STAT3 inhibitors have been evaluated in in vivo models and have led to tumor reduction. Taken together, these studies suggest that targeting SH2 domains is an important approach to the treatment of breast cancer.

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Structural Basis of Binding by Cyclic Nonphosphorylated Peptide Antagonists of Grb7 Implicated in Breast Cancer Progression

Cited by 21 publications

References 49 publications

Targeting GRB7/ERK/FOXM1 Signaling Pathway Impairs Aggressiveness of Ovarian Cancer Cells

Targeting GRB7/ERK/FOXM1 Signaling Pathway Impairs Aggressiveness of Ovarian Cancer Cells

Water-Refined Solution Structure of the Human Grb7-SH2 Domain in Complex with the erbB2 Receptor Peptide pY1139

Targeting Sh2 Domains in Breast Cancer

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