The WW Domain of Neural Protein FE65 Interacts with Proline-rich Motifs in Mena, the Mammalian Homolog of DrosophilaEnabled

Ermekova, Kira S.; Zambrano, Nicola; Linn, Hillary; Minopoli, Giuseppina; Gertler, Frank B.; Russo, Tommaso; Sudol, Marius

doi:10.1074/jbc.272.52.32869

Cited by 222 publications

(189 citation statements)

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“…Furthermore, this PTB1 domain of Fe65 binds the N-terminal domain of Tau protein and their interaction is regulated by Tau phosphorylation (15). The WW domain of FE65 binds the prolinecontaining motif of Mena, the mammalian homolog of enabled, which is involved in the control of cell motility through regulation of the actin cytoskeleton (16). Another ligand of the WW domain is the c-Abl tyrosine kinase, which phosphorylates APP on Tyr-682 (17,18) and Fe65 on Tyr-547, within the PTB2 domain (19).…”

Section: The Adaptor Protein Fe65mentioning

confidence: 99%

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Fe65 matters: New light on an old molecule

et al. 2012

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SummaryThe discovery that the main constituents of amyloid deposits, characteristic of Alzheimer neuropathology, derive from the proteolytic processing of the membrane precursor amyloid precursor protein (APP) is one of the milestones of the research history of this disease. Despite years of intense studies, the functions of APP and of its amyloidogenic processing are still under debate. One focus of these studies was the complex network of protein-protein interactions centered at the cytosolic domain of APP, which suggests the involvement of APP in a lively signaling pathway. Fe65 was the first protein to be demonstrated to interact with the APP cytodomain. Starting from this observation, a large body of data has been gathered, indicating that Fe65 is an adaptor protein, which binds numerous proteins, further than APP. Among these proteins, the crosstalk with Mena, mDab, and Abl suggested the involvement of the Fe65-APP complex in the regulation of cell motility, with a relevant role in differentiation and development. Other partners, like the histone acetyltransferase Tip60, indicated the possibility that the nuclear fraction of Fe65 could be involved in gene regulation and/or DNA repair.2012 IUBMB IUBMB Life, 64(12): 936-942, 2012

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Section: The Adaptor Protein Fe65mentioning

confidence: 99%

“…Mena was the first protein identified to interact with the WW domain of Fe65 (16). Mena belongs to a small family of proteins involved in the control of cell movement and morphology and in chemotactic responses (37).…”

Section: Fe65 Cytoskeleton Remodeling and Cell Movementmentioning

confidence: 99%

Fe65 matters: New light on an old molecule

et al. 2012

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“…The upper panel shows complexes assembled on the proline-rich segment of Mena, a protein implicated in the control of micro®lament dynamics. Src and Abl SH3 domains, pro®lin, and the WW domain of the FE65 adapter protein, recognize identical (or closely overlapping) PPLP cores in Mena (Ermekova et al, 1997;Gertler et al, 1996). The polyproline motifs in Mena represent potential points of convergence for several signal transduction pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylation of the signature tyrosine in the ligand (PP6Y) prevents the formation of the complex (Chen et al, 1997). Group II WW domains bind ligands containing PPLP cores usually surrounded by at least three additional prolines distributed between f N and f C sequences (Bedford et al, 1997; Ermekova et al, 1997). The e determinant here allows for easy prediction between these two groups.…”

Section: Ww Rulesmentioning

confidence: 99%

“…In addition, many physiological binders of pro®lin, including Mena, VASP, cdc12p, p140m Dia and Cappucino, all contain long runs of prolines interrupted or terminated by leucine (Mahoney et al, 1997). It is the PPLP core(s) of Mena that interact(s) with the WW domain of the FE65 adapter protein linked to the Alzheimer's beta amyloid precursor (Ermekova et al, 1997). The same PPLP core interacts with selected SH3 domains including those of Src and Abl, and in a longer context of¯anking prolines, with pro®lin (Gertler et al, 1996;Figure 4).…”

Section: Degeneracy In The`protein Recognition Code'mentioning

confidence: 99%

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From Src Homology domains to other signaling modules: proposal of the `protein recognition code'

1998

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The study of oncogenes has illuminated many aspects of cellular signaling. The delineation and characterization of protein modules exempli®ed by Src Homology domains has revolutionized our understanding of the molecular events underlying signal transduction pathways. Several well characterized intracellular modules which mediate protein-protein interactions, namely SH2, SH3, PH, PTB, EH, PDZ, EVH1 and WW domains, are directly involved in the multitude of membrane, cytoplasmic and nuclear processes in multicellular and/or unicellular organisms. The modular character of these protein domains and their cognate motifs, the universality of their molecular function, their widespread occurrence, and the speci®city as well as the degeneracy of their interactions have prompted us to propose the concept of the`protein recognition code'. By a parallel analogy to the universal genetic code, we propose here that there will be a ®nite set of precise rules to govern and predict protein-protein interactions mediated by modules. Several rules of the`protein recognition code' have already emerged.

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Alternatively spliced isoforms of FE65 serve as neuron-specific and non-neuronal markers

Hu¹,

Hearn²,

Jin³

et al. 1999

J. Neurosci. Res.

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FE65 is predominantly expressed in brain and is especially rich in the regions with the highest densities of neurons. The FE65 protein binds to an intracellular domain of the beta-amyloid precursor protein (betaPP) and may modulate the production of beta-amyloid peptide (AP). One of FE65 exons, a mini-exon (exon 9, 6 bp), is alternatively spliced, giving rise to two isoforms varying only in 6 base pairs. We quantitated the two isoforms by a sensitive reverse transcription-competitive polymerase chain reaction technique, and characterized their expressions in various tissues and cell cultures, and the kinetics of expression of the two isoforms in P19 embryonal carcinoma cell lines during neuronal differentiation. Our results show that the exon 9-inclusive (E9) form, the more abundant form in brain, was exclusively expressed in neurons, while the exon 9-exclusive (DeltaE9) form was widely expressed in all non-neuronal cells, but was not expressed in differentiated neurons. When P19 cells were differentiated to neurons, expression of FE65 was significantly up regulated ( approximately 30-fold) and the splicing pattern of the FE65 pre-mRNA was switched from the DeltaE9 pattern to the E9 form. Based upon their distinctive expression patterns, these two isoforms may serve as neuronal and non-neuronal markers, and determination of their ratios may have applications in neuropathological diagnosis.

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The WW Domain of Neural Protein FE65 Interacts with Proline-rich Motifs in Mena, the Mammalian Homolog of DrosophilaEnabled

Cited by 222 publications

References 56 publications

Fe65 matters: New light on an old molecule

Fe65 matters: New light on an old molecule

From Src Homology domains to other signaling modules: proposal of the `protein recognition code'

Alternatively spliced isoforms of FE65 serve as neuron-specific and non-neuronal markers

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