BBA - Molecular Cell Research (v.1783, #2)

Polarized growth of the neuron would logically require some form of membrane traffic to the tip of the growth cone, regulated in conjunction with other trafficking processes that are common to both neuronal and non-neuronal cells. Unlike axons, dendrites are endowed with membranous organelles of the exocytic pathway extending from the cell soma, including both rough and smooth endoplasmic reticulum (ER) and the ER–Golgi intermediate compartment (ERGIC). Dendrites also have satellite Golgi-like cisternal stacks known as Golgi outposts that have no membranous connections with the somatic Golgi. Golgi outposts presumably serve both general and specific local trafficking needs, and could mediate membrane traffic required for polarized dendritic growth during neuronal differentiation. Recent findings suggest that dendritic growth, but apparently not axonal growth, relies very much on classical exocytic traffic, and is affected by defects in components of both the early and late secretory pathways. Within dendrites, localized processes of recycling endosome-based exocytosis regulate the growth of dendritic spines and postsynaptic compartments. Emerging membrane traffic processes and components that contribute specifically to dendritic growth are discussed.
Keywords: Dendrite; Golgi apparatus; Golgi outpost; Neuron; Sar 1; Syntaxin 16;

Molecular mimicry: Structural camouflage of proteins and nucleic acids by Panagiotis A. Tsonis; Bhakti Dwivedi (177-187).
When it comes to protein specificity and function their three-dimensional structure is the ultimate determinant. Thus, sequences that participate in key parts, such as catalytic sites or DNA binding have been favored and maintained highly conserved during evolution. However, in a reversal of fortune, selection has favored conservation of shapes over sequence, especially when proteins look like nucleic acids. Proteins from pathogens evade the host's defenses because they are shaped as DNA; others use such a disguise for transcriptional regulation. Several factors are tRNA look-alikes so that they can efficiently control the process of protein synthesis. Molecular mimicry among RNAs could result in a new unexplored level in gene regulation. This comprehensive review outlines this important area and aims to emphasize that molecular mimicry could in fact be more widespread than initially thought and eventually adds a new layer of genetic regulation.
Keywords: Molecular mimicry; Protein–DNA; RNA–tRNA; Protein–tRNA;

The microtubule-associated protein tau is phosphorylated by Syk by Thibaud Lebouvier; Timothy M.E. Scales; Diane P. Hanger; Robert L. Geahlen; Bernard Lardeux; C. Hugh Reynolds; Brian H. Anderton; Pascal Derkinderen (188-192).
Aberrant phosphorylation of tau protein on serine and threonine residues has been shown to be critical in neurodegenerative disorders called tauopathies. An increasing amount of data suggest that tyrosine phosphorylation of tau might play an equally important role in pathology, with at least three putative tyrosine kinases of tau identified to date. It was recently shown that the tyrosine kinase Syk could efficiently phosphorylate α-synuclein, the aggregated protein found in Parkinson's disease and other synucleinopathies. We report herein that Syk is also a tau kinase, phosphorylating tau in vitro and in CHO cells when both proteins are expressed exogenously. In CHO cells, we have also demonstrated by co-immunoprecipitation that Syk binds to tau. Finally, by site-directed mutagenesis substituting the tyrosine residues of tau with phenylalanine, we established that tyrosine 18 was the primary residue in tau phosphorylated by Syk. The identification of Syk as a common tyrosine kinase of both tau and α-synuclein may be of potential significance in neurodegenerative disorders and also in neuronal physiology. These results bring another clue to the intriguing overlaps between tauopathies and synucleinopathies and provide new insights into the role of Syk in neuronal physiology.
Keywords: Tau; Tyrosine phosphorylation; Syk; Tauopathy;

Telomeres are dynamic DNA–protein complexes at the end of linear chromosomes. Maintenance of functional telomeres is required for chromosome stability, and to avoid the activation of DNA damage response pathway and cell cycle arrest. Telomere-binding proteins play crucial roles in the maintenance of functional telomeres. In this study, we employed affinity pull-down and proteomic approach to search for novel proteins that interact with the single-stranded telomeric DNA. The proteins identified by two-dimensional gel electrophoresis were further characterized by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and MALDI-TOF-TOF tandem MS. Among the five identified proteins, we report here the biochemical properties of a novel protein, hnRNP A3. The purified hnRNP A3 bound specifically to G-rich strand, but not to C-rich strand or double-stranded telomeric DNA. The RRM1 (RNA recognition motif 1) domain, but not RRM2, of hnRNP A3 is sufficient to confer specific binding to the telomeric sequence. In addition, we present evidence that hnRNP A3 can inhibit telomerase extension in vitro. These biochemical properties of hnRNP A3 suggest that hnRNP A3 can participate in telomere regulation in vivo.
Keywords: Telomere; Telomerase; hnRNP A3; Telomere-binding protein; RNA recognition motif;

Translin is a conserved protein which associates with the breakpoint junctions of chromosomal translocations linked with the development of some human cancers. It binds to both DNA and RNA and has been implicated in mRNA metabolism and regulation of genome stability. It has a binding partner, translin-associated protein X (TRAX), levels of which are regulated by the translin protein in higher eukaryotes. In this study we find that this regulatory function is conserved in the lower eukaryotes, suggesting that translin and TRAX have important functions which provide a selective advantage to both unicellular and multi-cellular eukaryotes, indicating that this function may not be tissue-specific in nature. However, to date, the biological importance of translin and TRAX remains unclear. Here we systematically investigate proposals that suggest translin and TRAX play roles in controlling mitotic cell proliferation, DNA damage responses, genome stability, meiotic/mitotic recombination and stability of GT-rich repeat sequences. We find no evidence for translin and/or TRAX primary function in these pathways, indicating that the conserved biochemical function of translin is not implicated in primary pathways for regulating genome stability and/or segregation.
Keywords: Translin; Trax; Schizosaccharomyces pombe; Genome stability;

Stringent time-dependent transregulation of calcium calmodulin kinase II (CaMKII) is implicated in anti-apoptotic control by Michael Fährmann; Sarah Honisch; Marc-André Kaufhold; Michael Leitges; Winfried Beil (214-223).
Induction of apoptosis by the PP1/PP2A inhibitor calyculin A was inhibited if the CaMKII inhibitor KN-93 was added no later than 10 min after addition of calyculin A. The physiological relevance and mechanism of CaMKII during apoptosis, however, remains largely unclear. Here we show in MDCK and gastric parietal cells that normal transregulation of CaMKII terminates the initial burst of autophosphorylation after only 10 min. The kinetics of CaMKII involved transregulation by PP1, PP2A, PP2B and PKCα. Transregulation of CaMKII resulted in two kinetic phases for phosphorylation of the autoactivation site at T286/287. During the initial phase, there was a clear peak of phosphorylation that lasted 10 min. This phase was subsequently followed by a half but constant level of T286/287 phosphorylation. Calyculin A perturbed this transregulation, resulting in a hyperphosphorylated CaMKII. This effect of CA on the kinetics of CaMKII was observed in vivo as well as in vitro using isolated tubulovesicles. Calyculin A-induced hyperphosphorylation of CaMKII appears to be at least one mechanism used by cells to trigger apoptosis. Therefore, stringent limitation of CaMKII autophosphorylation at T286/287 by transregulation and prevention of hyperphosphorylation seems to restrict apoptosis.
Keywords: Adaptation; Apoptosis; Ca2+/calmodulin-dependent protein kinase II (CaMKII); Proteinphosphatases; Protein kinase C (PKC); Signal transduction;

The orphan nuclear receptor Rev-erbβ recruits Tip60 and HDAC1 to regulate apolipoprotein CIII promoter by Jiadong Wang; Nansong Liu; Zhongle Liu; Yang Li; Chi Song; Hanying Yuan; Yu-yang Li; Xin Zhao; Hong Lu (224-236).
Nuclear hormone receptors function as ligand activated transcription factors. Ligand binding and modification such as acetylation have been reported to regulate nuclear hormone receptors. The orphan receptors, Rev-erbα and Rev-erbβ, are members of the nuclear receptor superfamily and act as transcriptional repressors. In this study, the role of recruitment of co-factors by Rev-erbβ and acetylation of Rev-erbβ in modulating apolipoprotein CIII (apoCIII) transcription were investigated. Rev-erbβ was found to transcriptionally repress apoCIII after binding to the apoCIII promoter. Tip60, a histone acetyl-transferase (HAT), was a novel binding partner for Rev-erbβ and recruited to the apoCIII promoter by Rev-erbβ. Tip60 was able to acetylate Rev-erbβ and relieve the apoCIII repression mediated by Rev-erbβ. This de-repression effect depended on acetylation of Rev-erbβ at its RXKK motif by Tip60. In addition, histone deacetylase 1 (HDAC1) interacted with Rev-erbβ and was recruited to the apoCIII promoter by Rev-erbβ to antagonize Tip60's activity. Taken together, we have provided evidence that Rev-erbβ modulates the apoCIII gene expression by recruiting different transcription co-activator or co-repressor.
Keywords: Orphan nuclear receptor Rev-erbβ; Tip60; Apolipoprotein CIII; HDAC1; Acetylation;

A large family of aldo-keto reductases with similar kinetic and structural properties but unknown physiological roles is expressed in the yeast Saccharomyces cerevisiae. Strains with one or two AKR genes disrupted have apparently normal phenotypes, but disruption of at least three AKR genes results in a heat shock phenotype and slow growth in inositol-deficient culture medium (Ino). The present study was carried out to identify metabolic or signaling defects that may underlie phenotypes that emerge in AKR deficient strains. Here we demonstrate that pretreatment of a pentuple AKR null mutant with the anti-oxidative agent N-acetyl-cysteine rescues the heat shock phenotype. This indicates that AKR gene disruption may be associated with defects in oxidative stress response. We observed additional markers of oxidative stress in AKR-deficient strains, including reduced glutathione levels, constitutive nuclear localization of the oxidation-sensitive transcription factor Yap1 and upregulation of a set of Yap1 target genes whose function as a group is primarily involved in response to oxidative stress and redox balance. Genetic analysis of the Ino phenotype of the null mutants showed that defects in transcriptional regulation of the INO1, which encodes for inositol-1-phosphate synthase, can be rescued through ectopic expression of a functional INO1. Taken together, these results suggest potential roles for AKRs in oxidative defense and transcriptional regulation.
Keywords: Aldo-keto reductase; Inositol auxotrophy; Oxidative stress; Heat shock sensitivity;

HOIL-1 is not required for iron-mediated IRP2 degradation in HEK293 cells by Kimberly B. Zumbrennen; Eric S. Hanson; Elizabeth A. Leibold (246-252).
Iron regulatory protein 2 (IRP2) binds to iron-responsive elements (IREs) to regulate the translation and stability of mRNAs encoding several proteins involved in mammalian iron homeostasis. Increases in cellular iron stimulate the polyubiquitylation and proteasomal degradation of IRP2. One study has suggested that haem-oxidized IRP2 ubiquitin ligase-1 (HOIL-1) binds to a unique 73-amino acid (aa) domain in IRP2 in an iron-dependent manner to regulate IRP2 polyubiquitylation and degradation. Other studies have questioned the role of the 73-aa domain in iron-dependent IRP2 degradation. We investigated the potential role of HOIL-1 in the iron-mediated degradation of IRP2 in human embryonic kidney 293 (HEK293) cells. We found that transiently expressed HOIL-1 and IRP2 interact via the 73-aa domain, but this interaction is not iron-dependent, nor does it enhance the rate of IRP2 degradation by iron. In addition, stable expression of HOIL-1 does not alter the iron-dependent degradation or RNA-binding activity of endogenous IRP2. Reduction of endogenous HOIL-1 by siRNA has no affect on the iron-mediated degradation of endogenous IRP2. These data demonstrate that HOIL-1 is not required for iron-dependent degradation of IRP2 in HEK293 cells, and suggest that a HOIL-1 independent mechanism is used for IRP2 degradation in most cell types.
Keywords: Iron; IRP2; HOIL-1; Ubiquitylation; Degradation; HEK293;

Regulation of LPA receptor function by estrogens by Aliesha González-Arenas; S. Eréndira Avendaño-Vázquez; Alejandro Cabrera-Wrooman; Diana Tapia-Carrillo; Fernando Larrea; Rocío García-Becerra; J. Adolfo García-Sáinz (253-262).
17β-Estradiol induced LPA1 receptor desensitization in C9 cells stably expressing LPA1 receptors and transiently expressing estrogen receptor α. Such desensitization was evidenced by a reduction in lysophosphatidic acid-mediated Ca2+mobilization and it was associated to receptor phosphorylation and internalization. These effects of 17β-estradiol were rapid (taking place over 5 min) and were blocked by the estrogen receptor antagonist ICI 182780. Similarly, inhibitors of phosphoinositide 3-kinase (wortmannin and LY294002) and of protein kinase C (staurosporine and Gö 6976) blocked 17β-estradiol-induced LPA1 receptor desensitization and phosphorylation. Confocal microscopy evidenced LPA1 receptor internalization in response to 17β-estradiol treatment. Association between LPA1 receptors and protein kinase C α was suggested by co-immunoprecipitation assays. Protein kinase C α was associated with LPA1 receptors in the absence of stimulus and such association further increased in a dynamic fashion in response to 17β-estradiol. The results demonstrated that in C9 cells estrogens modulate LPA1 action through estrogen receptor α with the participation of protein kinase C α and phosphoinositide 3-kinase.
Keywords: LPA1 receptor; PKC; PI3K; 17-β; estradiol; ERα; GPCR;

TIP30 (Tat-interacting protein 30), a newly found proapoptotic factor, appears to be involved in multiple functions including metabolic suppression, apoptosis induction, and diminishing angiogenic properties. In the present study, we reported that mitochondrial events were required for apoptosis induced by TIP30 in hepatocellular carcinoma cells (HCC cells). Translocation of Bax was essential for TIP30-induced apoptosis, whereas overexpression of the anti-apoptotic protein Bcl-xL delayed both second mitochondria-derived activator of caspases (Smac/DIABLO) release and onset of apoptosis. Furthermore, TIP30-induced apoptosis was dependent on caspase activity because the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone (z-VAD-fmk) blocked DNA fragmentation. Release of Smac/DIABLO from the mitochondria through the TIP30–P53–Bax cascade was required to remove the inhibitory effect of XIAP (X-linked Inhibitor of Apoptosis) and allowed apoptosis to proceed. Our results showed for the first time that Bax-dependent release of Smac/DIABLO, cytochrome c and AIF from the mitochondria mediated the contribution of the mitochondrial pathway to TIP30-mediated apoptosis. Our data suggested that adenovirus-mediated overexpression of TIP30 was capable of inducing therapeutic programmed cell death in vitro by activating the mitochondrial pathway of apoptosis. On the basis of these studies, elucidating the mechanism by which TIP30 induces cell death might establish it as an anticancer approach.
Keywords: Hepatocellular carcinoma; TIP30; Bax; Bcl-xL; Cytochrome c; Smac/DIABLO;

Multimerisation of receptor-type protein tyrosine phosphatases PTPBR7 and PTP-SL attenuates enzymatic activity by Yvet E. Noordman; Eveline D. Augustus; Jan T.G. Schepens; Renato G.S. Chirivi; Pablo Ríos; Rafael Pulido; Wiljan J.A.J. Hendriks (275-286).
Dimerisation of receptor-type protein tyrosine phosphatases (RPTPs) represents an appealing mechanism to regulate their enzymatic activity. Studies thus far mostly concern the dimerisation behaviour of RPTPs possessing two tandemly oriented catalytic PTP domains. Mouse gene Ptprr encodes four different protein isoforms (i.e. PTPBR7, PTP-SL and PTPPBSγ-42/37) that contain a single PTP domain. Using selective membrane permeabilisation we here demonstrate that PTP-SL, like PTPBR7, is a single membrane-spanning RPTP. Furthermore, these two receptor-type PTPs constitutively formed homo- and hetero-meric complexes as witnessed in chemical cross-linking and co-immunoprecipitation experiments, in sharp contrast to the cytosolic PTPPBSγ-42 and PTPPBSγ-37 PTPRR isoforms. This multimerisation occurs independently of the PTP domain and requires the transmembrane domain and/or the proximal hydrophobic region. Using overexpression of a PTPBR7 mutant that essentially lacks the intracellular PTP domain-containing segment, a monomer-mimicking state was forced upon full-length PTPBR7 immunoprecipitates. This resulted in a significant increase in the enzymatic activity of the PTPRR PTP domain, which strengthens the notion that multimerisation represents a general mechanism to tone down RPTP catalytic activity.
Keywords: Dimerisation; Hydrophobic region; Phosphatase activity; Protein topology; PTPRR; DifMUP;

Suppression of FUT1/FUT4 expression by siRNA inhibits tumor growth by Zhenbo Zhang; Ping Sun; Jiwei Liu; Li Fu; Jie Yan; Yuejian Liu; Lihua Yu; Xiaoqi Wang; Qiu Yan (287-296).
Lewis Y (LeY) antigen is highly expressed in a variety of human carcinomas of epithelial cell origin. Recent studies suggest functional blockade of LeY may provide a novel therapeutic approach for the treatment of cancers. However, suppressing LeY expression by genetic manipulation and its impact on neoplastic cell proliferation has not been investigated. We report here that different fucosyltransferases (FUTs) were expressed with the greatest expression of fucosyltransferase I or IV (FUT1/4), the two key enzymes for the synthesis of LeY in human epidermoid carcinoma A431 cells. Knocking down FUT1/4 expression by short interfering RNA technique dramatically reduced the expression of FUT1/4 and LeY and inhibited cell proliferation through decreasing epidermal growth factor receptor (EGFR) signaling pathway. Treatment of A431 cells that were inoculated into the nude mice with FUT1 siRNA or FUT4 siRNA greatly impeded tumor growth. Suppressing FUT1/4 expression also blocked EGF-induced tyrosine phosphorylation of EGFR and mitogen-activated protein kinases. In conclusion, suppressing the expression of FUT1/4 by RNAi technology reduces the synthesis of LeY and inhibits cancer growth. It may serve as a potential methodology for the treatment of cancers that express LeY glycoconjugates.
Keywords: Fucosyltransferase; siRNA; Tumor growth; Lewis antigen;

S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA2 by Saeid Ghavami; Claus Kerkhoff; Walter J. Chazin; Kamran Kadkhoda; Wenyan Xiao; Anne Zuse; Mohammad Hashemi; Mehdi Eshraghi; Klaus Schulze-Osthoff; Thomas Klonisch; Marek Los (297-311).
A complex of two S100 EF-hand calcium-binding proteins S100A8/A9 induces apoptosis in various cells, especially tumor cells. Using several cell lines, we have shown that S100A8/A9-induced cell death is not mediated by the receptor for advanced glycation endproducts (RAGE), a receptor previously demonstrated to engage S100 proteins. Investigation of cell lines either deficient in, or over-expressing components of the death signaling machinery provided insight into the S100A8/A9-mediated cell death pathway. Treatment of cells with S100A8/A9 caused a rapid decrease in the mitochondrial membrane potential (ΔΨ m) and activated Bak, but did not cause release of apoptosis-inducing factor (AIF), endonuclease G (Endo G) or cytochrome c. However, both Smac/DIABLO and Omi/HtrA2 were selectively released into the cytoplasm concomitantly with a decrease in Drp1 expression, which inhibits mitochondrial fission machinery. S100A8/A9 treatment also resulted in decreased expression of the anti-apoptotic proteins Bcl2 and Bcl-XL, whereas expression of the pro-apoptotic proteins Bax, Bad and BNIP3 was not altered. Over-expression of Bcl2 partially reversed the cytotoxicity of S100A8/A9. Together, these data indicate that S100A8/A9-induced cell death involves Bak, selective release of Smac/DIABLO and Omi/HtrA2 from mitochondria, and modulation of the balance between pro- and anti-apoptotic proteins.
Keywords: Bcl2 protein family; S100/calgranulin; Cancer regression; Drp1; Receptor for advanced glycated endproducts (RAGE); Mitochondrial fission; XIAP;

Cystatin B and its EPM1 mutants are polymeric and aggregate prone in vivo by Elena Cipollini; Massimo Riccio; Rossella Di Giaimo; Fabrizio Dal Piaz; Giuseppe Pulice; Sandra Catania; Ilaria Caldarelli; Maja Dembic; Spartaco Santi; Marialuisa Melli (312-322).
Progressive myoclonus epilepsy type 1 (EPM1) is a neurodegenerative disease correlating with mutations of the cystatin B gene. Cystatin B is described as a monomeric protein with antiprotease function. This work shows that, in vivo, cystatin B has a polymeric structure, highly resistant to SDS, urea, boiling and sensitive to reducing agents and alkaline pH. Hydrogen peroxide increases the polymeric structure of the protein. Mass spectrometry analysis shows that the only component of the polymers is cystatin B. EPM1 mutants of cystatin B transfected in cultured cells are also polymeric. The banding pattern generated by a cysteine-minus mutant is different from that of the wild-type protein as it contains only monomers, dimers and some very high MW bands while misses components of MW intermediate between 25 and 250 kDa. Overexpression of wild-type or EPM1 mutants of cystatin B in neuroblastoma cells generates cytoplasmic aggregates. The cysteine-minus mutant is less prone to the formation of inclusion bodies. We conclude that cystatin B in vivo has a polymeric structure sensitive to the redox environment and that overexpression of the protein generates aggregates. This work describes a protein with a physiological role characterized by highly stable polymers prone to aggregate formation in vivo.
Keywords: Polymers; Cystatin B; Cellular aggregates; EPM1; Neurodegeneration; Cytoskeleton;

HIF-1α controls keratinocyte proliferation by up-regulating p21(WAF1/Cip1) by Young-Suk Cho; Jae-Moon Bae; Yang-Sook Chun; Jin-Ho Chung; Yoon-Kyung Jeon; In-San Kim; Myung-Suk Kim; Jong-Wan Park (323-333).
The cyclin-dependent kinase inhibitor p21WAF1/Cip1 plays a central role in a spatial and temporal balance of epidermal keratinocyte proliferation and growth arrest. However, what controls p21 expression in keratinocytes remains uncertain. Hypoxia-inducible factor 1α (HIF-1α) does not only express a variety of genes essential for hypoxic adaptation, but also up-regulates p21 so as to slow down cell cycle under hypoxic conditions. In the present study, we examined the role of HIF-1α in p21-mediated growth arrest of keratinocyte. Keratinocyte proliferation was arrested in the G1 phase at a high cell density. p21 was also up-regulated in a cell density-dependent manner and was found to be highly expressed in epidermal keratinocytes of normal human skins. In addition, in the same specimens and cells, we noted robust HIF-1α expression. HIF-1α siRNAs inhibited p21 expression and released the G1 arrest. In vivo, moreover, the intradermal injection of HIF-1α siRNA attenuated p21 expression in rat epidermis and induced skin hyperplasia. Mechanistically, we propose that the production of mitochondrial reactive oxygen species and the activation of the MEK/ERK pathway are involved in the HIF-1α stabilization in keratinocytes. These results imply that HIF-1α functions as an up-stream player in the p21-mediated growth arrest of keratinocytes.
Keywords: Hypoxia-inducible factor 1α; p21; Keratinocyte; Cell density; Growth arrest;

Ezrin is a specific and direct target of protein tyrosine phosphatase PRL-3 by Eleonora Forte; Laura Orsatti; Fabio Talamo; Gaetano Barbato; Raffaele De Francesco; Licia Tomei (334-344).
Phosphatase of Regenerating Liver-3 (PRL-3) is a small protein tyrosine phosphatase considered an appealing therapeutic cancer target due to its involvement in metastatic progression. However, despite its importance, the direct molecular targets of PRL-3 action are not yet known. Here we report the identification of Ezrin as a specific and direct cellular substrate of PRL-3. In HCT116 colon cancer cell line, Ezrin was identified among the cellular proteins whose phosphorylation level decreased upon ectopic over-expression of wtPRL-3 but not of catalytically inactive PRL-3 mutants. Although PRL-3 over-expression in HCT116 cells appeared to affect Ezrin phosphorylation status at both tyrosine residues and Thr567, suppression of the endogenous protein by RNA interference pointed to Ezrin-Thr567 as the residue primarily affected by PRL-3 action. In vitro dephosphorylation assays suggested Ezrin-Thr567 as a direct substrate of PRL-3 also proving this enzyme as belonging to the dual specificity phosphatase family. Furthermore, the same effect on levels of pThr567, but not on pTyr residues, was observed in endothelial cells pointing to Ezrin-pThr567 dephosphorylation as a mean through which PRL-3 exerts its function in promoting tumor progression as well as in the establishment of the new vasculature needed for tumor survival and expansion.
Keywords: PTP; Substrate identification; Phosphorylation; ERM proteins; RNA interference;