scholarly journals TRIP6: An adaptor protein that regulates cell motility, antiapoptotic signaling and transcriptional activity

2011 ◽  
Vol 23 (11) ◽  
pp. 1691-1697 ◽  
Author(s):  
Victor T.G. Lin ◽  
Fang-Tsyr Lin
Keyword(s):  
Cell Motility ◽  
Transcriptional Activity ◽  
Adaptor Protein

scholarly journals Lysine acetyltransferase Tip60 acetylates the APP adaptor Fe65 to increase its transcriptional activity

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Sabine Probst ◽  
Florian Riese ◽  
Larissa Kägi ◽  
Maik Krüger ◽  
Natalie Russi ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Target Genes ◽  
Adaptor Protein ◽  
Proteolytic Processing ◽  
Class Iii ◽  
Lysine Deacetylase ◽  
Lysine Residues ◽  
Lysine Acetyltransferase ◽  
Complex Forms ◽  
Spot Formation

AbstractProteolytic processing of the amyloid precursor protein (APP) releases the APP intracellular domain (AICD) from the membrane. Bound to the APP adaptor protein Fe65 and the lysine acetyltransferase (KAT) Tip60, AICD translocates to the nucleus. Here, the complex forms spherical condensates at sites of endogenous target genes, termed AFT spots (AICD-Fe65-Tip60). We show that loss of Tip60 KAT activity prevents autoacetylation, reduces binding of Fe65 and abolishes Fe65-mediated stabilization of Tip60. Autoacetylation is a prerequisite for AFT spot formation, with KAT-deficient Tip60 retained together with Fe65 in speckles. We identify lysine residues 204 and 701 of Fe65 as acetylation targets of Tip60. We do not detect acetylation of AICD. Mutation of Fe65 K204 and K701 to glutamine, mimicking acetylation-induced charge neutralization, increases the transcriptional activity of Fe65 whereas Tip60 inhibition reduces it. The lysine deacetylase (KDAC) class III Sirt1 deacetylates Fe65 and pharmacological modulation of Sirt1 activity regulates Fe65 transcriptional activity. A second acetylation/deacetylation cycle, conducted by CBP and class I/II KDACs at different lysine residues, regulates stability of Fe65. This is the first report describing a role for acetylation in the regulation of Fe65 transcriptional activity, with Tip60 being the only KAT tested that supports AFT spot formation.

Adaptor protein XB130 is a Rac-controlled component of lamellipodia that regulates cell motility and invasion

2010 ◽  
Vol 123 (23) ◽  
pp. 4156-4169 ◽  
Author(s):  
Monika Lodyga ◽  
Xiao-hui Bai ◽  
András Kapus ◽  
Mingyao Liu
Keyword(s):  
Cell Motility ◽  
Adaptor Protein

The RNA-binding and adaptor protein Sam68 modulates signal-dependent splicing and transcriptional activity of the androgen receptor

2008 ◽  
Vol 215 (1) ◽  
pp. 67-77 ◽  
Author(s):  
P Rajan ◽  
L Gaughan ◽  
C Dalgliesh ◽  
A El-Sherif ◽  
CN Robson ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Transcriptional Activity ◽  
Rna Binding ◽  
Adaptor Protein

scholarly journals Signaling through ShcA Is Required for Transforming Growth Factor β- and Neu/ErbB-2-Induced Breast Cancer Cell Motility and Invasion

2008 ◽  
Vol 28 (10) ◽  
pp. 3162-3176 ◽  
Author(s):  
Jason J. Northey ◽  
Juliann Chmielecki ◽  
Elaine Ngan ◽  
Caterina Russo ◽  
Matthew G. Annis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cell Motility ◽  
Cancer Cells ◽  
Mammary Tumor ◽  
Breast Cancer Cells ◽  
Transforming Growth Factor ◽  
Adaptor Protein ◽  
Transforming Growth Factor Β ◽  
Migration And Invasion

ABSTRACT Cooperation between the Neu/ErbB-2 and transforming growth factor β (TGF-β) signaling pathways enhances the invasive and metastatic capabilities of breast cancer cells; however, the underlying mechanisms mediating this synergy have yet to be fully explained. We demonstrate that TGF-β induces the migration and invasion of mammary tumor explants expressing an activated Neu/ErbB-2 receptor, which requires signaling from autophosphorylation sites located in the C terminus. A systematic analysis of mammary tumor explants expressing Neu/ErbB-2 add-back receptors that couple to distinct signaling molecules has mapped the synergistic effect of TGF-β-induced motility and invasion to signals emanating from tyrosine residues 1226/1227 and 1253 of Neu/ErbB-2. Given that the ShcA adaptor protein is known to interact with Neu/ErbB-2 through these residues, we investigated the importance of this signaling molecule in TGF-β-induced cell motility and invasion. The reduction of ShcA expression rendered cells expressing activated Neu/ErbB-2, or add-back receptors signaling specifically through tyrosines 1226/1227 or 1253, unresponsive to TGF-β-induced motility and invasion. In addition, a dominant-negative form of ShcA, lacking its three known tyrosine phosphorylation sites, completely abrogates the TGF-β-induced migration and invasion of breast cancer cells expressing activated Neu/ErbB-2. Our results implicate signaling through the ShcA adaptor as a key component in the synergistic interaction between these pathways.

scholarly journals The Heat-Shock Protein Apg-2 Binds to the Tight Junction Protein ZO-1 and Regulates Transcriptional Activity of ZONAB

2006 ◽  
Vol 17 (3) ◽  
pp. 1322-1330 ◽  
Author(s):  
Anna Tsapara ◽  
Karl Matter ◽  
Maria S. Balda
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Tight Junction ◽  
Intracellular Signaling ◽  
Transcriptional Activity ◽  
Adaptor Protein ◽  
Sh3 Domain ◽  
Nucleic Acid Binding ◽  
Junction Protein

The tight junction adaptor protein ZO-1 regulates intracellular signaling and cell proliferation. Its Src homology 3 (SH3) domain is required for the regulation of proliferation and binds to the Y-box transcription factor ZO-1-associated nucleic acid binding protein (ZONAB). Binding of ZO-1 to ZONAB results in cytoplasmic sequestration and hence inhibition of ZONAB's transcriptional activity. Here, we identify a new binding partner of the SH3 domain that modulates ZO-1–ZONAB signaling. Expression screening of a cDNA library with a fusion protein containing the SH3 domain yielded a cDNA coding for Apg-2, a member of the heat-shock protein 110 (Hsp 110) subfamily of Hsp70 heat-shock proteins, which is overexpressed in carcinomas. Regulated depletion of Apg-2 in Madin-Darby canine kidney cells inhibits G1/S phase progression. Apg-2 coimmunoprecipitates with ZO-1 and partially localizes to intercellular junctions. Junctional recruitment and coimmunoprecipitation with ZO-1 are stimulated by heat shock. Apg-2 competes with ZONAB for binding to the SH3 domain in vitro and regulates ZONAB's transcriptional activity in reporter gene assays. Our data hence support a model in which Apg-2 regulates ZONAB function by competing for binding to the SH3 domain of ZO-1 and suggest that Apg-2 functions as a regulator of ZO-1–ZONAB signaling in epithelial cells in response to cellular stress.

The Acetyl-Transferase Tip60 Interacts with c-Myb and Inactivates Its Transcriptional Activity in Human Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3981-3981
Author(s):  
Huiwu Zhao ◽  
Shenghao Jin ◽  
Alan M. Gewirtz
Keyword(s):  
Histone Deacetylases ◽  
Transcriptional Activity ◽  
Hematopoietic Cells ◽  
Adaptor Protein ◽  
K562 Cells ◽  
Luciferase Reporter ◽  
Transactivation Domain ◽  
Interacting Protein ◽  
Factor C

Abstract Abstract 3981 Poster Board III-917 The acetyl-transferaseTip60 (Tat interacting protein, 60 kDa; also known as K(lysine) acetyltransferase 5:KAT5) is a co-regulator of transcription factors and is implicated in tumorigenesis. The protooncogene c-myb encodes a transcription factor, c-Myb, which is essential for normal hematopoisis and promotes hematologic malignancies. In this study, we explored potential regulatory relationships between Tip60 and c-Myb in hematopoietic cells. We first sought to detect any direct physical interactions by performing co-immunoprecitation (co-IP) assays. These revealed that Tip60 associated with c-Myb in Jurkat (T leukemia) and K562 (CML) cells. In vitro translated, epitope-tagged c-Myb and Tip60 also interacted with each other, suggesting that the Tip60, c-Myb interaction did not require an adaptor protein or co-factor. We then sought to define the interacting protein domains. Deletion analysis studies revealed that the interaction between Tip60 and c-Myb was dependent on the Tip60 MYST acetytransferase domain and transactivation domain of c-Myb. We then determined whether Tip60 could acetylate c-Myb, a post-translational event known to modulate c-Myb activity. Interestingly, an in vitro acetyltransferase assay showed that c-Myb was not a substrate of Tip60, even though Tip60 acetylated itself in the same assay. We then examined the effect of Tip60 on the ability of c-Myb to transcriptionally activate known target genes. In HEK293T cells, co-expressing Tip60 with c-Myb decreased c-Myb's ability to activate a luciferase reporter driven by the cim-1 promoter, a verified c-Myb target, by ∼60% compared to activation in the absence of Tip60. The physiologic significance of this observation was then explored. A chromatin immunoprecipiation (ChIP) assay revealed that Tip60 bound to the c-myc promoter, another known c-Myb target gene, in K562 cells. Furthermore, inactivation of endogenous c-Myb in K562 cells stably expressing an inducible c-Myb DNA binding domain reduced the occupancy of Tip60 in the c-myc promoter, suggesting that Tip60 utilizes c-Myb to bind its preferred site in the c-myc promoter. Using c-Myb, Tip60, and appropriate control siRNAs we achieved specific knockdowns of c-Myb, and Tip60 (∼80-90%, and ∼70-80% respectively compared to controls). Consistent with prior reports, c-myc expression decreased ∼60% when c-Myb was targeted, and ∼50% increased when Tip60 was targeted. A mechanistic explanation was sought to explain this finding. Tip60 is represses transcription when associated with histone deacetylases (HDAC), including HDAC1, HDAC2 and HDAC7. Co-IP of Jurkat cell lysates revealed that c-Myb is associated with HDAC1 and HDAC2. Altogether, these data suggest that Tip60 directly associates with c-Myb, and may inhibit its transcriptional activity by recruiting histone deacetylases(HDAC1 and HDAC2) to the activation complex. Finally, we compared Tip60 expression in 6 primary AML samples, with 3 normal CD34+ cell samples using QRT-PCR. Tip60 expression was significantly (∼60%) lower in the AML samples. In summary, these studies demonstrate that Tip60 modulates c-Myb transcriptional activity in human hematopoietic cells leading us to hypothesize that Tip60 is a normal regulator of c-Myb function and that dysregulated or mutated Tip60 may contribute to c-Myb driven leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Functional Characterization of Obesity-Associated Variants Involving the α and β Isoforms of Human SH2B1

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3219-3226 ◽  
Author(s):  
Laura R. Pearce ◽  
Ray Joe ◽  
Michael E. Doche ◽  
Hsiao-Wen Su ◽  
Julia M. Keogh ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Cell Motility ◽  
Neurite Outgrowth ◽  
Functional Characterization ◽  
Adaptor Protein ◽  
Maladaptive Behavior ◽  
In Vitro Assays ◽  
Nerve Growth ◽  
The Individual

Abstract We have previously reported rare variants in sarcoma (Src) homology 2 (SH2) B adaptor protein 1 (SH2B1) in individuals with obesity, insulin resistance, and maladaptive behavior. Here, we identify 4 additional SH2B1 variants by sequencing 500 individuals with severe early-onset obesity. SH2B1 has 4 alternatively spliced isoforms. One variant (T546A) lies within the N-terminal region common to all isoforms. As shown for past variants in this region, T546A impairs SH2B1β enhancement of nerve growth factor-induced neurite outgrowth, and the individual with the T546A variant exhibits mild developmental delay. The other 3 variants (A663V, V695M, and A723V) lie in the C-terminal tail of SH2B1α. SH2B1α variant carriers were hyperinsulinemic but did not exhibit the behavioral phenotype observed in individuals with SH2B1 variants that disrupt all isoforms. In in vitro assays, SH2B1α, like SH2B1β, enhances insulin- and leptin-induced insulin receptor substrate 2 (IRS2) phosphorylation and GH-induced cell motility. None of the variants affect SH2B1α enhancement of insulin- and leptin-induced IRS2 phosphorylation. However, T546A, A663V, and A723V all impair the ability of SH2B1α to enhance GH-induced cell motility. In contrast to SH2B1β, SH2B1α does not enhance nerve growth factor-induced neurite outgrowth. These studies suggest that genetic variants that disrupt isoforms other than SH2B1β may be functionally significant. Further studies are needed to understand the mechanism by which the individual isoforms regulate energy homeostasis and behavior.

scholarly journals PEAK3/C19orf35 pseudokinase, a new NFK3 kinase family member, inhibits CrkII through dimerization

2019 ◽  
Vol 116 (31) ◽  
pp. 15495-15504 ◽  
Author(s):  
Mitchell L. Lopez ◽  
Megan Lo ◽  
Jennifer E. Kung ◽  
Małgorzata Dudkiewicz ◽  
Gwendolyn M. Jang ◽  
...  
Keyword(s):  
Cell Motility ◽  
Family Member ◽  
Cancer Progression ◽  
Family Members ◽  
Adaptor Protein ◽  
Dimerization Domain ◽  
Unique Role ◽  
Membrane Ruffling ◽  
Kinase Family ◽  
Evolutionarily Conserved

Members of the New Kinase Family 3 (NKF3), PEAK1/SgK269 and Pragmin/SgK223 pseudokinases, have emerged as important regulators of cell motility and cancer progression. Here, we demonstrate that C19orf35 (PEAK3), a newly identified member of the NKF3 family, is a kinase-like protein evolutionarily conserved across mammals and birds and a regulator of cell motility. In contrast to its family members, which promote cell elongation when overexpressed in cells, PEAK3 overexpression does not have an elongating effect on cell shape but instead is associated with loss of actin filaments. Through an unbiased search for PEAK3 binding partners, we identified several regulators of cell motility, including the adaptor protein CrkII. We show that by binding to CrkII, PEAK3 prevents the formation of CrkII-dependent membrane ruffling. This function of PEAK3 is reliant upon its dimerization, which is mediated through a split helical dimerization domain conserved among all NKF3 family members. Disruption of the conserved DFG motif in the PEAK3 pseudokinase domain also interferes with its ability to dimerize and subsequently bind CrkII, suggesting that the conformation of the pseudokinase domain might play an important role in PEAK3 signaling. Hence, our data identify PEAK3 as an NKF3 family member with a unique role in cell motility driven by dimerization of its pseudokinase domain.

scholarly journals Role for a Cindr–Arf6 axis in patterning emerging epithelia

2011 ◽  
Vol 22 (23) ◽  
pp. 4513-4526 ◽  
Author(s):  
Ruth I. Johnson ◽  
Alanna Sedgwick ◽  
Crislyn D'Souza-Schorey ◽  
Ross L. Cagan
Keyword(s):  
Cell Motility ◽  
Adaptor Protein ◽  
Time Lapse ◽  
Similar Relationship ◽  
Surface Adhesion ◽  
Cell Movements ◽  
Surface Receptors ◽  
Time Lapse Microscopy ◽  
Gtpase Activating Proteins ◽  
Regulatory Cascade

Patterning of the Drosophila pupal eye is characterized by precise cell movements. In this paper, we demonstrate that these movements require an Arf regulatory cycle that connects surface receptors to actin-based movement. dArf6 activity—regulated by the Arf GTPase–activating proteins (ArfGAPs) dAsap and dArfGAP3 and the Arf GTP exchange factors Schizo and dPsd—promoted large cellular extensions; time-lapse microscopy indicated that these extensions presage cell rearrangements into correct epithelial niches. During this process, the Drosophila eye also requires interactions between surface Neph1/nephrin adhesion receptors Roughest and Hibris, which bind the adaptor protein Cindr (CD2AP). We provide evidence that Cindr forms a physical complex with dArfGAP3 and dAsap. Our data suggest this interaction sequesters ArfGAP function to liberate active dArf6 elsewhere in the cell. We propose that a Neph1/nephrin–Cindr/ArfGAP complex accumulates to limit local Arf6 activity and stabilize adherens junctions. Our model therefore links surface adhesion via an Arf6 regulatory cascade to dynamic modeling of the cytoskeleton, accounting for precise cell movements that organize the functional retinal field. Further, we demonstrate a similar relationship between the mammalian Cindr orthologue CD2AP and Arf6 activity in cell motility assays. We propose that this Cindr/CD2AP-mediated regulation of Arf6 is a widely used mechanism in emerging epithelia.

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