Disease relevance of NEDD9

• Regulation of NEDD9 may be an important means whereby atRA promotes cell spreading and neurite outgrowth in SH-SY5Y human neuroblastoma cells, and NEDD9 represents a new downstream target of atRA and its receptors in the developing hindbrain [1].
• Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene [2].
• HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells [3].
• Three cellular proteins, including species of 300,000 daltons and 107,000 daltons as well as p105-RB, the product of the retinoblastoma susceptibility gene, stably interact with the adenovirus E1A proteins [4].
• Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention [5].
• Mechanistic studies suggest diverse cellular roles of HEF1 and highlight its importance in the response to extracellular cues that drive invasion and metastasis [6].

Psychiatry related information on NEDD9

• The absence of a relation between the periconceptional use of vitamins and neural-tube defects. National Institute of Child Health and Human Development Neural Tube Defects Study Group [7].
• Three-dimensional computergraphic analysis of apraxia. Neural representations of learned movement [8].
• Mechanisms that underlie figural emergence support the interpolation of contours and the filling-in of form information [Grossberg, S., & Mingolla, E. Neural dynamics of form perception: Boundary completion, illusory figures and neon colour spreading. Psychological Review, 92, 173-211, 1985] [9].
• CONCLUSIONS: Neural activity within the medial and lateral orbitofrontal cortex, pregenual ACC, and striatum mediate distinct representations of reward-related information that are deployed at different stages during a decision-making episode [10].
• Immunoreactivity of the nuclear antigen p105 is associated with plaques and tangles in Alzheimer's disease [11].

High impact information on NEDD9

• A series of functional, biochemical, and clinical studies established NEDD9 as a bona fide melanoma metastasis gene [2].
• NEDD9 enhanced invasion in vitro and metastasis in vivo of both normal and transformed melanocytes, functionally interacted with focal adhesion kinase and modulated focal contact formation, and exhibited frequent robust overexpression in human metastatic melanoma relative to primary melanoma [2].
• The association between the retinoblastoma protein (p105-RB) and either the large T antigen of SV40 or the E1A proteins of adenovirus is thought to be an important step in transformation by these viral oncogenes [12].
• p105-RB is the product of the retinoblastoma tumor suppressor gene [13].
• It is synthesized as approximately 100K protein (p100) that is expressed in different cell types, contains cell cycle motifs and, like p105, must be processed to generate a 50K form [14].

Chemical compound and disease context of NEDD9

• Crk-associated substrate (Cas) family member, NEDD9, is regulated in human neuroblastoma cells and in the embryonic hindbrain by all-trans retinoic acid [1].
• Letter: Neural crest, limb development, and thalidomide embryopathy [15].
• Synthesis of p105 was not blocked by phosphonoacetic acid and could be induced in Raji cells by superinfection with virus derived from P3HR1 cells [16].
• CONCLUSION: Neural networks provide a potentially useful tool in the decision-making task to discriminate patients with AD and cocaine abuse from normal controls [17].
• 17 beta-estradiol inhibits tumor necrosis factor-alpha-induced nuclear factor-kappa B activation by increasing nuclear factor-kappa B p105 level in MCF-7 breast cancer cells [18].

Biological context of NEDD9

• A putative retinoic acid response element in the 5' region of the NEDD9 promoter binds specifically to a RXR/RAR heterodimer and forms a higher molecular weight complex upon addition of a retinoic acid receptor-specific antibody [1].
• Regulation of HEF1 expression and phosphorylation by TGF-beta 1 and cell adhesion [19].
• The TGF-beta1-induced HEF1 expression was independent of cell adhesion and resistant to cytoskeleton disruption [19].
• Human enhancer of filamentation 1 (HEF1) has been implicated in signaling pathways such as those mediated by integrin, T cell receptor, and B cell receptor and functions as a multidomain docking protein [20].
• Integration of high-resolution copy number profiles of mouse tumor models and human tumors identified cIAP1 and Yap as oncogenes in human hepatocellular carcinoma, while NEDD9 was identified as a metastasis gene in human melanoma [21].

Anatomical context of NEDD9

• NEDD9 is expressed in the developing hindbrain (5-somite stage) in the presumptive rhombomeres 2, 3, and 5 before the onset of overt segmentation [1].
• T cell receptor-mediated tyrosine phosphorylation of Cas-L, a 105-kDa Crk-associated substrate-related protein, and its association of Crk and C3G [22].
• Our studies reveal that TGF-beta1 is a potent inducer of HEF1 gene transcription in human dermal fibroblasts [19].
• Further, whereas p130cas is localized predominantly at focal adhesions, immunofluorescence indicates that HEF1 localizes to both the cell periphery and the cell nucleus and is differently localized in fibroblasts and epithelial cells, suggesting a more complex role in cell signalling [23].
• Interestingly, pretreatment of tonsillar B cells with cytochalasin B dramatically reduced both integrin- and BCR-induced HEF1 phosphorylation, suggesting that some component of the BCR-mediated signaling pathway is closely linked with a cytoskeletal reorganization [24].

Associations of NEDD9 with chemical compounds

• NEDD9 expression is also perturbed in vitamin A-deficient embryos [1].
• Human enhancer of filamentation-1 (HEF1), a multifunctional docking protein, is involved in integrin-based signaling, which affects cell motility, growth, and apoptosis [19].
• While the generation of the cleaved HEF1 forms is caspase dependent, the accumulation of HEF1 forms is further regulated by the proteasome, as the proteasome inhibitors N-acetyl-L-leucinyl-L-leucinyl-L-norleucinyl and lactacystin enhance their stability [25].
• Dibutyryl cAMP and forskolin had little or no effect on HEF1 phosphorylation, and the protein kinase A inhibitor H89 failed to detectably inhibit the response to calcitonin, indicating that the G(s)/cAMP/protein kinase A pathway does not mediate the calcitonin effect [26].
• Phorbol 12-myristate 13-acetate also induced HEF1 tyrosine phosphorylation, and the protein kinase C inhibitor calphostin C completely inhibited both calcitonin- and phorbol 12-myristate 13-acetate-stimulated HEF1 phosphorylation [26].

Physical interactions of NEDD9

• These results suggest that MICAL may be a cytoskeletal regulator that connects CasL to intermediate filaments [27].
• Our studies revealed that Smad3 interacts with HEF1 and triggers the proteasomal degradation of HEF1 in overexpression systems [28].
• This association is mediated by the LIM region of the zyxin family members and the SH2 domain-binding region of CasL/HEF1 [29].
• G protein-coupled receptors in gastrointestinal physiology. IV. Neural regulation of gastrointestinal smooth muscle [30].

Co-localisations of NEDD9

• MICAL is a cytoplasmic protein and colocalizes with CasL at the perinuclear area [27].
• The phosphorylated HEF1 colocalized with vinculin and was associated almost exclusively with 0.1% Triton X-100 insoluble material, consistent with its signaling at focal adhesions [3].

Regulatory relationships of NEDD9

• The molecular mechanisms underlying Smad3-regulated HEF1 degradation are not well understood [31].
• Focal adhesion kinase regulates beta1 integrin-dependent T cell migration through an HEF1 effector pathway [32].
• Analysis of a series of beta1 cytoplasmic domain truncations reveals that a truncation of only five amino acids from the carboxyl-terminal end of the beta1 cytoplasmic domain abrogates the ability of the CD2/beta1 chimera to activate tyrosine phosphorylation of HEF1, pp105, or pp115 [33].
• The HEF1-promoted processes are dependent on the presence of an intact microtubule system and can be inhibited by co-expression of either constitutively active Rac or Cdc42 GTPase [34].

Other interactions of NEDD9

• TGF-beta1 had no effect on the stability of either HEF1 protein or mRNA [19].
• Here we report our studies that demonstrate the function of AIP4 as an ubiquitin E3 ligase for HEF1 [20].
• Exposure of rat embryos to excess atRA at times ranging from E9.25 to E12 leads to altered NEDD9 expression in the developing hindbrain within 6 hr [1].
• Together, our results indicate that beta1 integrin-stimulated T cell migration requires a linear beta1 integrin-FAK-HEF1 effector pathway [32].
• MICAL associates with CasL through this PPKPP sequence [27].

Analytical, diagnostic and therapeutic context of NEDD9

• Here we show that ligation of either beta1 integrin or B cell antigen receptor (BCR) on human tonsillar B cells and B cell lines promoted tyrosine phosphorylation of HEF1 [24].
• Immunoblotting with specific antibodies revealed that pp120 and pp105 were identical to the c-cbl proto-oncogene product (p120cbl) and CasL, respectively [35].
• Anti-peptide antisera raised against human T-cadherin recognized a protein spot corresponding to the purified p105 on two-dimensional Western blots [36].
• Carbachol induced time-dependent increases in phosphotyrosine immunoreactivity of several protein bands, which were quantitated, and immunoprecipitation was used to identify the adhesion-related proteins focal adhesion kinase, p130Cas/HEF1, and paxillin, and three shc adapter proteins [37].
• The hematopoietic isoform of cas-hef1-associated signal transducer regulates chemokine-induced inside-out signaling and T cell trafficking [38].

References