scholarly journals Mutational Analysis of the pH Signal Transduction Component PalC of Aspergillus nidulans Supports Distant Similarity to BRO1 Domain Family Members

Genetics ◽  
2005 ◽  
Vol 171 (1) ◽  
pp. 393-401 ◽  
Author(s):  
Joan Tilburn ◽  
Juan C. Sánchez-Ferrero ◽  
Elena Reoyo ◽  
Herbert N. Arst ◽  
Miguel A. Peñalva
Keyword(s):  
Signal Transduction ◽  
Aspergillus Nidulans ◽  
Mutational Analysis ◽  
Family Members ◽  
Domain Family

scholarly journals Further Characterization of the Signaling Proteolysis Step in the Aspergillus nidulans pH Signal Transduction Pathway

2007 ◽  
Vol 6 (6) ◽  
pp. 960-970 ◽  
Author(s):  
María M. Peñas ◽  
América Hervás-Aguilar ◽  
Tatiana Múnera-Huertas ◽  
Elena Reoyo ◽  
Miguel Á. Peñalva ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Aspergillus Nidulans ◽  
Cysteine Protease ◽  
Mutational Analysis ◽  
Signal Transduction Pathway ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Western Blots ◽  
C Terminus ◽  
Catalytic Cysteine

ABSTRACT The Aspergillus nidulans pH-responsive transcription factor PacC is modulated by limited, two-step proteolysis. The first, pH-regulated cleavage occurs in the 24-residue highly conserved “signaling protease box” in response to the alkaline pH signal. This is transduced by the Pal signaling pathway, containing the predicted calpain-like cysteine protease and likely signaling protease, PalB. In this work, we carried out classical mutational analysis of the putative signaling protease PalB, and we describe 9 missense and 18 truncating loss-of-function (including null) mutations. Mutations in the region of and affecting directly the predicted catalytic cysteine strongly support the deduction that PalB is a cysteine protease. Truncating and missense mutations affecting the C terminus highlight the importance of this region. Analysis of three-hemagglutinin-tagged PalB in Western blots demonstrates that PalB levels are independent of pH and Pal signal transduction. We have followed the processing of MYC3-tagged PacC in Western blots. We show unequivocally that PalB is essential for signaling proteolysis and is definitely not the processing protease. In addition, we have replaced 15 residues of the signaling protease box of MYC3-tagged PacC (pacC900) with alanine. The majority of these substitutions are silent. Leu481Ala, Tyr493Ala, and Gln499Ala result in delayed PacC processing in response to shifting from acidic to alkaline medium, as determined by Western blot analysis. Leu498Ala reduces function much more markedly, as determined by plate tests and processing recalcitrance. Excepting Leu498, this demonstrates that PacC signaling proteolysis is largely independent of sequence in the cleavage region.

scholarly journals Characterization of the Kaposi's Sarcoma-Associated Herpesvirus K1 Signalosome

2005 ◽  
Vol 79 (19) ◽  
pp. 12173-12184 ◽  
Author(s):  
Bok-Soo Lee ◽  
Sun-Hwa Lee ◽  
Pinghui Feng ◽  
Heesoon Chang ◽  
Nam-Hyuk Cho ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Inflammatory Cytokines ◽  
Kaposi's Sarcoma ◽  
Mutational Analysis ◽  
Tyrosine Phosphatase ◽  
Kaposi’S Sarcoma ◽  
Sh2 Domain ◽  
Signaling Proteins ◽  
Cellular Signal ◽  
Cellular Components

ABSTRACT Kaposi's sarcoma (KS) is a multifocal angiogenic tumor and appears to be a hyperplastic disorder caused, in part, by local production of inflammatory cytokines. The K1 lymphocyte receptor-like protein of KS-associated herpesvirus (KSHV) efficiently transduces extracellular signals to elicit cellular activation events through its cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). To further delineate K1-mediated signal transduction, we purified K1 signaling complexes and identified its cellular components. Upon stimulation, the K1 ITAM was efficiently tyrosine phosphorylated and subsequently interacted with cellular Src homology 2 (SH2)-containing signaling proteins Lyn, Syk, p85, PLCγ2, RasGAP, Vav, SH2 domain-containing protein tyrosine phosphatase 1/2, and Grab2 through its phosphorylated tyrosine residues. Mutational analysis demonstrated that each tyrosine residue of K1 ITAM contributed to the interactions with cellular signaling proteins in distinctive ways. Consequently, these interactions led to the marked augmentation of cellular signal transduction activity, evidenced by the increase of cellular tyrosine phosphorylation and intracellular calcium mobilization, the activation of NF-AT and AP-1 transcription factor activities, and the production of inflammatory cytokines. These results demonstrate that KSHV K1 effectively recruits a set of cellular SH2-containing signaling molecules to form the K1 signalosome, which elicits downstream signal transduction and induces inflammatory cytokine production.

scholarly journals P1.09-006 JMJ and BRD Domain Family Members in Malignant Pleural Mesothelioma: Potential Therapeutic Targets or Not?

2017 ◽  
Vol 12 (11) ◽  
pp. S2019-S2020
Author(s):  
S. Gray ◽  
M. Breslin ◽  
S. Cregan ◽  
L. Quinn ◽  
S. Wennstedt ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Family Members ◽  
Therapeutic Targets ◽  
Pleural Mesothelioma ◽  
Domain Family

Prognostic and predictive value of Pleckstrin homology-like domain, family A family members in breast cancer

2020 ◽  
Vol 14 (16) ◽  
pp. 1537-1552
Author(s):  
Flavia R Mangone ◽  
Maira AV Valoyes ◽  
Renan G do Nascimento ◽  
Mércia PF Conceição ◽  
Daniel R Bastos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family Members ◽  
Therapy Response ◽  
In Silico Analysis ◽  
Tissue Microarrays ◽  
Luminal Breast Cancer ◽  
Pleckstrin Homology ◽  
Domain Family ◽  
Luminal A ◽  
New Information

Aim: The PHLDA (pleckstrin homology like domain, family A) gene family encodes proteins capable of inhibiting AKT (serine/threonine kinase) signaling through phosphoinositol binding competition. Results & methodology: Using in silico analysis, we found that Luminal A and B patients' short relapse-free survival was associated with low PHLDA1 or PHLDA3 and high PHLDA2 expression. In a cohort of 393 patients with luminal breast cancer evaluated by immunohistochemistry on tissue microarrays, we found a direct association of PHLDA3 expression with hormonal therapy response (p = 0.013). Conclusion: Our findings provide new information on the role played by the PHLDA family members as prognostic markers in breast cancer, and more importantly, we provide evidence that they might also predict a response to endocrine therapy.

Genome-wide identification and analysis of JHBP-domain family members in the silkworm Bombyx mori

2016 ◽  
Vol 291 (6) ◽  
pp. 2159-2171 ◽  
Author(s):  
Wei Li ◽  
Tingcai Cheng ◽  
Wenbo Hu ◽  
Zhangchuan Peng ◽  
Chun Liu ◽  
...  
Keyword(s):  
Bombyx Mori ◽  
Family Members ◽  
Domain Family ◽  
Genome Wide ◽  
Silkworm Bombyx Mori

scholarly journals The juxtamembrane regions of the epidermal growth factor receptor and gp185erbB-2 determine the specificity of signal transduction.

1991 ◽  
Vol 11 (6) ◽  
pp. 3191-3202 ◽  
Author(s):  
O Segatto ◽  
F Lonardo ◽  
D Wexler ◽  
F Fazioli ◽  
J H Pierce ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Mutational Analysis ◽  
Growth Factor Receptor ◽  
Tyrosine Kinase Domain ◽  
Amino Terminal ◽  
Epidermal Growth

The epidermal growth factor receptor (EGFR) and gp185erbB-2 are closely related tyrosine kinases. Despite extensive sequence and structural homology, these two receptors display quantitative and qualitative differences in their ability to couple with mitogenic signalling pathways. By using chimeric molecules between EGFR and erbB-2, we found that the determinants responsible for the specificity of mitogenic signal transduction are located in the amino-terminal half of the tyrosine kinase domain of either receptor. In the EGFR, mutational analysis within this subdomain revealed that deletion of residues 660 to 667 impaired receptor mitogenic activity without affecting its tyrosine kinase properties. This sequence is therefore likely to contribute to the specificity of substrate recognition by the EGFR kinase.

scholarly journals The BH3 Domain of Bcl-xS Is Required for Inhibition of the Antiapoptotic Function of Bcl-xL

1999 ◽  
Vol 19 (10) ◽  
pp. 6673-6681 ◽  
Author(s):  
Brian S. Chang ◽  
Ameeta Kelekar ◽  
Marian H. Harris ◽  
John E. Harlan ◽  
Stephen W. Fesik ◽  
...  
Keyword(s):  
Cell Death ◽  
Mammalian Cells ◽  
Mutational Analysis ◽  
Survival Function ◽  
Family Members ◽  
Protein Product ◽  
Deletion Mutants ◽  
Major Protein ◽  
Bh3 Domain ◽  
Acid Protein

ABSTRACT bcl-x is a member of the bcl-2 family of genes. The major protein product, Bcl-xL, is a 233-amino-acid protein which has antiapoptotic properties. In contrast, one of the alternatively spliced transcripts of the bcl-xgene codes for the protein Bcl-xS, which lacks 63 amino acids present in Bcl-xL and has proapoptotic activity. Unlike other proapoptotic Bcl-2 family members, such as Bax and Bak, Bcl-xS does not seem to induce cell death in the absence of an additional death signal. However, Bcl-xS does interfere with the ability of Bcl-xL to antagonize Bax-induced death in transiently transfected 293 cells. Mutational analysis of Bcl-xS was conducted to identify the domains necessary to mediate its proapoptotic phenotype. Deletion mutants of Bcl-xS which still contained an intact BH3 domain retained the ability to inhibit survival through antagonism of Bcl-xL. Bcl-xS was able to form heterodimers with Bcl-xL in mammalian cells, and its ability to inhibit survival correlated with the ability to heterodimerize with Bcl-xL. Deletion mutants of Bax and Bcl-2, which lacked BH1 and BH2 domains but contained a BH3 domain, were able to antagonize the survival effect conferred by Bcl-xL. The results suggest that BH3 domains from both pro- and antiapoptotic Bcl-2 family members, while lacking an intrinsic ability to promote programmed cell death, can be potent inhibitors of Bcl-xL survival function.

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