scholarly journals A Novel Interaction between the SH2 Domain of Signaling Adaptor Protein Nck-1 and the Upstream Regulator of the Rho Family GTPase Rac1 Engulfment and Cell Motility 1 (ELMO1) Promotes Rac1 Activation and Cell Motility

2014 ◽  
Vol 289 (33) ◽  
pp. 23112-23122 ◽  
Author(s):  
Guo Zhang ◽  
Xia Chen ◽  
Fanghua Qiu ◽  
Fengxin Zhu ◽  
Wenjing Lei ◽  
...  
Keyword(s):  
Cell Motility ◽  
Adaptor Protein ◽  
Sh2 Domain ◽  
Upstream Regulator ◽  
Rho Family

scholarly journals Phosphorylation of Tyrosine Residues 31 and 118 on Paxillin Regulates Cell Migration through an Association with Crk in Nbt-II Cells

2000 ◽  
Vol 148 (5) ◽  
pp. 957-970 ◽  
Author(s):  
Valérie Petit ◽  
Brigitte Boyer ◽  
Delphine Lentz ◽  
Christopher E. Turner ◽  
Jean Paul Thiery ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Critical Role ◽  
Adaptor Protein ◽  
Signaling Molecules ◽  
Sh2 Domain ◽  
Wild Type ◽  
Tyrosine Residues ◽  
Pathological Conditions

Identification of signaling molecules that regulate cell migration is important for understanding fundamental processes in development and the origin of various pathological conditions. The migration of Nara Bladder Tumor II (NBT-II) cells was used to determine which signaling molecules are specifically involved in the collagen-mediated locomotion. We show here that paxillin is tyrosine phosphorylated after induction of motility on collagen. Overexpression of paxillin mutants in which tyrosine 31 and/or tyrosine 118 were replaced by phenylalanine effectively impaired cell motility. Moreover, stimulation of motility by collagen preferentially enhanced the association of paxillin with the SH2 domain of the adaptor protein CrkII. Mutations in both tyrosine 31 and 118 diminished the phosphotyrosine content of paxillin and prevented the formation of the paxillin–Crk complex, suggesting that this association is necessary for collagen-mediated NBT-II cell migration. Other responses to collagen, such as cell adhesion and spreading, were not affected by these mutations. Overexpression of wild-type paxillin or Crk could bypass the migration-deficient phenotype. Both the SH2 and the SH3 domains of CrkII are shown to play a critical role in this collagen-mediated migration. These results demonstrate the important role of the paxillin–Crk complex in the collagen-induced cell motility.

scholarly journals R-cadherin influences cell motility via Rho family GTPases. Vol. 279 (2004) 31041-31049

2004 ◽  
Vol 279 (42) ◽  
pp. 44229-44230
Author(s):  
Emhonta Johnson ◽  
Christopher S. Theisen ◽  
Keith R. Johnson ◽  
Margaret J. Wheelock
Keyword(s):  
Cell Motility ◽  
Rho Family Gtpases ◽  
Rho Family

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

Expression level and differential JAK2-V617F–binding of the adaptor protein Lnk regulates JAK2-mediated signals in myeloproliferative neoplasms

Blood ◽  
2010 ◽  
Vol 116 (26) ◽  
pp. 5961-5971 ◽  
Author(s):  
Fanny Baran-Marszak ◽  
Hajer Magdoud ◽  
Christophe Desterke ◽  
Anabell Alvarado ◽  
Claudine Roger ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Adaptor Protein ◽  
Jak2 V617f ◽  
Negative Control ◽  
Sh2 Domain ◽  
Expression Level ◽  
Activating Mutations ◽  
Thrombopoietin Receptor ◽  
Dependent Cell

Abstract Activating mutations in signaling molecules, such as JAK2-V617F, have been associated with myeloproliferative neoplasms (MPNs). Mice lacking the inhibitory adaptor protein Lnk display deregulation of thrombopoietin/thrombopoietin receptor signaling pathways and exhibit similar myeloproliferative characteristics to those found in MPN patients, suggesting a role for Lnk in the molecular pathogenesis of these diseases. Here, we showed that LNK levels are up-regulated and correlate with an increase in the JAK2-V617F mutant allele burden in MPN patients. Using megakaryocytic cells, we demonstrated that Lnk expression is regulated by the TPO-signaling pathway, thus indicating an important negative control loop in these cells. Analysis of platelets derived from MPN patients and megakaryocytic cell lines showed that Lnk can interact with JAK2-WT and V617F through its SH2 domain, but also through an unrevealed JAK2-binding site within its N-terminal region. In addition, the presence of the V617F mutation causes a tighter association with Lnk. Finally, we found that the expression level of the Lnk protein can modulate JAK2-V617F–dependent cell proliferation and that its different domains contribute to the inhibition of multilineage and megakaryocytic progenitor cell growth in vitro. Together, our results indicate that changes in Lnk expression and JAK2-V617F–binding regulate JAK2-mediated signals in MPNs.

scholarly journals ELOTUZUMAB FOR THE TREATMENT OF RELAPSED OR REFRACTORY MULTIPLE MYELOMA, WITH SPECIAL REFERENCE TO ITS MODES OF ACTION AND SLAMF7 SIGNALING

2018 ◽  
Vol 10 (1) ◽  
pp. e2018014 ◽  
Author(s):  
Masafumi Taniwaki ◽  
Mihoko Yoshida ◽  
Yosuke Matsumoto ◽  
Kazuho Shimura ◽  
Junya Kuroda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cell ◽  
Cell Activity ◽  
Adaptor Protein ◽  
Progression Free Survival ◽  
Sh2 Domain ◽  
Phase Iii ◽  
Refractory Multiple Myeloma ◽  
Pathway Activation ◽  
Signaling Lymphocytic Activation Molecule

Elotuzumab, targeting signaling lymphocytic activation molecule family 7 (SLAMF7), has been approved in combination with lenalidomide and dexamethasone   (ELd)   for relapsed/refractory  multiple myeloma (MM) based on the findings of the phase III randomized trial  ELOQUENT-2 (NCT01239797). Four-year  follow-up  analyses  of  ELOQUENT-2 have demonstrated  that  progression-free survival was 21%  in  ELd  versus  14%  in  Ld. Elotuzumab binds a unique epitope on the membrane IgC2 domain of SLAMF7, exhibiting a dual mechanism of  action:  natural  killer  (NK)  cell-mediated  antibody-dependent  cellular  cytotoxicity  (ADCC) and  enhancement  of  NK  cell  activity.  The  ADCC  is  mediated  through  engagement  between  Fc portion  of  elotuzumab  and  FcgRIIIa/CD16  on  NK  cells. Enhanced NK cell cytotoxicity results fromm phosphorylation  of  the  immunoreceptor  tyrosine-based  switch  motif  (ITSM)  that  is induced via elotuzumab binding and recruits the SLAM-associated adaptor protein EAT-2.The coupling of EAT-2 to the phospholipase Cg enzymes SH2 domain leads to enhanced Ca2+. Influx and MAPK/Erk pathway activation, resulting in granule polarization and enhanced exocytosis inNK  cells. Elotuzumab  does not stimulate the  proliferation of MM cells due to a lack of EAT-2.The  inhibitory  effects  of  elotuzumab  on  MM  cell  growth  are  not  induced by  the lack  of  CD45, even  though  SHP-2,  SHP-1,  SHIP-1,  and  Csk may be  recruited  to  phosphorylated  ITSM  of SLAMF7.  ELd  improves PFS in patients  with  high-risk  cytogenetics,  i.e.  t(4;14),  del(17p),  and 1q21  gain/amplification. Since  the immune  state  is  paralytic  in  advanced  MM,  the  efficacy  of ELd with minimal toxicity may bring forward for consideration of its use in the early stages of the disease.

scholarly journals Fibronectin-stimulated signaling from a focal adhesion kinase-c-Src complex: involvement of the Grb2, p130cas, and Nck adaptor proteins.

1997 ◽  
Vol 17 (3) ◽  
pp. 1702-1713 ◽  
Author(s):  
D D Schlaepfer ◽  
M A Broome ◽  
T Hunter
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Intracellular Signaling ◽  
Protein Tyrosine Kinase ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Sh2 Domain ◽  
Mitogen Activated Protein Kinase

The focal adhesion kinase (FAK), a protein-tyrosine kinase (PTK), associates with integrin receptors and is activated by cell binding to extracellular matrix proteins, such as fibronectin (FN). FAK autophosphorylation at Tyr-397 promotes Src homology 2 (SH2) domain binding of Src family PTKs, and c-Src phosphorylation of FAK at Tyr-925 creates an SH2 binding site for the Grb2 SH2-SH3 adaptor protein. FN-stimulated Grb2 binding to FAK may facilitate intracellular signaling to targets such as ERK2-mitogen-activated protein kinase. We examined FN-stimulated signaling to ERK2 and found that ERK2 activation was reduced 10-fold in Src- fibroblasts, compared to that of Src- fibroblasts stably reexpressing wild-type c-Src. FN-stimulated FAK phosphotyrosine (P.Tyr) and Grb2 binding to FAK were reduced, whereas the tyrosine phosphorylation of another signaling protein, p130cas, was not detected in the Src- cells. Stable expression of residues 1 to 298 of Src (Src 1-298, which encompass the SH3 and SH2 domains of c-Src) in the Src- cells blocked Grb2 binding to FAK; but surprisingly, Src 1-298 expression also resulted in elevated p130cas P.Tyr levels and a two- to threefold increase in FN-stimulated ERK2 activity compared to levels in Src- cells. Src 1-298 bound to both FAK and p130cas and promoted FAK association with p130cas in vivo. FAK was observed to phosphorylate p130cas in vitro and could thus phosphorylate p130cas upon FN stimulation of the Src 1-298-expressing cells. FAK-induced phosphorylation of p130cas in the Src 1-298 cells promoted the SH2 domain-dependent binding of the Nck adaptor protein to p130cas, which may facilitate signaling to ERK2. These results show that there are additional FN-stimulated pathways to ERK2 that do not involve Grb2 binding to FAK.

scholarly journals Molecular Interplay between AURKA and SPOP Dictates CRPC Pathogenesis via Androgen Receptor

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3247
Author(s):  
Kumar Nikhil ◽  
Mohini Kamra ◽  
Asif Raza ◽  
Hanan S. Haymour ◽  
Kavita Shah
Keyword(s):  
Androgen Receptor ◽  
Feedback Loop ◽  
Adaptor Protein ◽  
Castration Resistant Prostate Cancer ◽  
Wild Type ◽  
Protein Levels ◽  
Upstream Regulator ◽  
Castration Resistant ◽  
Tumor Enhancer

SPOP, an adaptor protein for E3 ubiquitin ligase can function as a tumor-suppressor or a tumor-enhancer. In castration-resistant prostate cancer (CRPC), it inhibits tumorigenesis by degrading many oncogenic targets, including androgen receptor (AR). Expectedly, SPOP is the most commonly mutated gene in CRPC (15%), which closely correlates with poor prognosis. Importantly, 85% of tumors that retain wild-type SPOP show reduced protein levels, indicating that SPOP downregulation is an essential step in CRPC progression. However, the underlying molecular mechanism remains unknown. This study uncovered the first mechanism of SPOP regulation in any type of cancer. We identified SPOP as a direct substrate of Aurora A (AURKA) using an innovative technique. AURKA directly phosphorylates SPOP at three sites, causing its ubiquitylation. SPOP degradation drives highly aggressive oncogenic phenotypes in cells and in vivo including stabilizing AR, ARv7 and c-Myc. Further, SPOP degrades AURKA via a feedback loop. SPOP upregulation is one of the mechanisms by which enzalutamide exerts its efficacy. Consequently, phospho-resistant SPOP fully abrogates tumorigenesis and EMT in vivo, and renders CRPC cells sensitive to enzalutamide. While genomic mutations of SPOP can be treated with gene therapy, identification of AURKA as an upstream regulator of SPOP provides a powerful opportunity for retaining WT-SPOP in a vast majority of CRPC patients using AURKA inhibitors ± enzalutamide, thereby treating the disease and inhibiting its progression.

Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3403-3411 ◽  
Author(s):  
Johan Dixelius ◽  
Helena Larsson ◽  
Takako Sasaki ◽  
Kristina Holmqvist ◽  
Lingge Lu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Adaptor Protein ◽  
Sh2 Domain ◽  
Heparin Binding ◽  
Collagen Gels ◽  
Tyrosine Kinase Activity ◽  
Binding Ability ◽  
Collagen Xviii

Abstract Endostatin, which corresponds to the C-terminal fragment of collagen XVIII, is a potent inhibitor of angiogenesis. Fibroblast growth factor-2 (FGF-2)–induced angiogenesis in the chicken chorioallantoic membrane was inhibited by endostatin, but not by an endostatin mutant R158/270A, lacking heparin-binding ability. Endostatin was internalized by endothelial cells, but not by mouse fibroblasts. Treatment of murine brain endothelial (IBE) cells with endostatin reduced the proportion of cells in S phase, whereas growth-arrested IBE cells in collagen gels treated with endostatin displayed enhanced tubular morphogenesis. IBE cells overexpressing Shb, an adaptor protein implicated in angiostatin-induced apoptosis, displayed elevated apoptosis and decreased tubular morphogenesis in collagen gels in response to endostatin when added together with FGF-2. Induction of apoptosis was dependent on the heparin-binding ability of endostatin and the expression of Shb with a functional Src homology 2 (SH2)-domain. Endostatin treatment for 10 minutes or 24 hours induced tyrosine phosphorylation of Shb and formation of multiprotein complexes. An Shb SH2 domain fusion protein precipitated a 125-kd phosphotyrosyl protein in endostatin-treated cells. The 125-kd component either contained intrinsic tyrosine kinase activity or occurred in complex with a tyrosine kinase. In conclusion, our data show that endostatin induces tyrosine kinase activity and enhanced apoptosis in FGF-treated endothelial cells.

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