Hua Zhang

Imperial College London, Londinium, England, United Kingdom

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Publications (5)43.18 Total impact

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    ABSTRACT: Lemur tyrosine kinase 3 (LMTK3) is associated with cell proliferation and endocrine resistance in breast cancer. We found that, in cultured breast cancer cell lines, LMTK3 promotes the development of a metastatic phenotype by inducing the expression of genes encoding integrin subunits. Invasive behavior in various breast cancer cell lines positively correlated with the abundance of LMTK3. Overexpression of LMTK3 in a breast cancer cell line with low endogenous LMTK3 abundance promoted actin cytoskeleton remodeling, focal adhesion formation, and adhesion to collagen and fibronectin in culture. Using SILAC (stable isotope labeling by amino acids in cell culture) proteomic analysis, we found that LMTK3 increased the abundance of integrin subunits α5 and β1, encoded by ITGA5 and ITGB1. This effect depended on the CDC42 Rho family guanosine triphosphatase, which was in turn activated by the interaction between LMTK3 and growth factor receptor-bound protein 2 (GRB2), an adaptor protein that mediates receptor tyrosine kinase-induced activation of RAS and downstream signaling. Knockdown of GRB2 suppressed LMTK3-induced CDC42 activation, blocked ITGA5 and ITGB1 expression promoted by the transcription factor serum response factor (SRF), and reduced invasive activity. Furthermore, abundance of LMTK3 positively correlated with that of the integrin β1 subunit in breast cancer patient's tumors. Our findings suggest a role for LMTK3 in promoting integrin activity during breast cancer progression and metastasis.
    Science Signaling 01/2014; 7(330):ra58. · 7.65 Impact Factor
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    ABSTRACT: Protein kinases play a pivotal role in regulating many aspects of biological processes, including development, differentiation and cell death. Within the kinome, 48 kinases (~10%) are classified as pseudokinases owing to the fact that they lack at least one conserved catalytic residue in their kinase domain. However, emerging evidence suggest that some pseudokinases, even without the ability to phosphorylate substrates, are regulators of multiple cellular signalling pathways. Among these is KSR1 (kinase suppressor of Ras 1), which was initially identified as a novel kinase in the Ras/Raf pathway. Subsequent studies showed that KSR1 mainly functions as a platform to assemble different cellular components thereby facilitating signal transduction. In the present article, we discuss recent findings regarding KSR1, indicating that it has dual activity as an active kinase as well as a pseudokinase/scaffolding protein. Moreover, the biological functions of KSR1 in human disorders, notably in malignancies, are also reviewed.
    Biochemical Society Transactions 08/2013; 41(4):1078-82. · 2.59 Impact Factor
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    ABSTRACT: Estrogen Receptor α (ERα), a member of the nuclear receptor superfamily of transcription factors, plays a central role in breast cancer development. More than two-thirds of patients with breast cancer are ERα-positive; however, a proportion becomes resistant. Phosphorylation of ERα is one of the mechanisms associated with resistance to endocrine therapy. In a kinome screen, we have identified the large tumor suppressor homolog-2 (LATS2) as a potential kinase, acting on ERα. The role of LATS2 on activation of ERα transcription and its functional consequences was examined by various molecular and cellular biology techniques. LATS2 co-localises with ERα in the nucleus. LATS2-silencing increases expression of ERα-regulated genes and inhibits proliferation. At the protein level, inhibition of LATS2 reduces the expression of cyclin-D1 and Nuclear Receptor Co-Repressor (NCoR) while increasing the expression of p27. Identifying novel kinases which modulate ERα activity is relevant to therapeutics. LATS2 modulates ERα-regulated gene transcription, through direct and/or indirect interactions with ERα.
    Anticancer research 01/2013; 33(1):53-63. · 1.71 Impact Factor
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    ABSTRACT: Kinases play a critical role in regulating many cellular functions including development, differentiation and proliferation. To date, over 518 proteins with kinase activity, comprising ~2-3% of total cellular proteins, have been identified from within the human kinome. Interestingly, approximately 10% of kinases are categorised as pseudokinases since they lack one or more conserved catalytic residues within their kinase domain and were originally thought to have no enzymatic activity. Recently, there has been strong evidence to suggest that some pseudokinsases can not only function as scaffold proteins, but may also possess kinase activity leading to modulation of cell signalling pathways. Altered activity of these pseudokinases can result in impaired cellular function, particularly in malignancies. In this review we are discussing recent evidence that apart from a scaffolding role, pseudokinases also orchestrate cellular processes as active kinases per se in signalling pathways of malignant cells.
    Cellular signalling 02/2012; 24(6):1173-84. · 4.09 Impact Factor
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    ABSTRACT: Therapies targeting estrogen receptor α (ERα, encoded by ESR1) have transformed the treatment of breast cancer. However, large numbers of women relapse, highlighting the need for the discovery of new regulatory targets modulating ERα pathways. An siRNA screen identified kinases whose silencing alters the estrogen response including those previously implicated in regulating ERα activity (such as mitogen-activated protein kinase and AKT). Among the most potent regulators was lemur tyrosine kinase-3 (LMTK3), for which a role has not previously been assigned. In contrast to other modulators of ERα activity, LMTK3 seems to have been subject to Darwinian positive selection, a noteworthy result given the unique susceptibility of humans to ERα+ breast cancer. LMTK3 acts by decreasing the activity of protein kinase C (PKC) and the phosphorylation of AKT (Ser473), thereby increasing binding of forkhead box O3 (FOXO3) to the ESR1 promoter. LMTK3 phosphorylated ERα, protecting it from proteasomal degradation in vitro. Silencing of LMTK3 reduced tumor volume in an orthotopic mouse model and abrogated proliferation of ERα+ but not ERα- cells, indicative of its role in ERα activity. In human cancers, LMTK3 abundance and intronic polymorphisms were significantly associated with disease-free and overall survival and predicted response to endocrine therapies. These findings yield insights into the natural history of breast cancer in humans and reveal LMTK3 as a new therapeutic target.
    Nature medicine 06/2011; 17(6):715-9. · 27.14 Impact Factor