scholarly journals Kindlin2 regulates neural crest specification via integrin-independent regulation of the FGF signaling pathway

Development ◽  
2021 ◽  
Author(s):  
Hui Wang ◽  
Chengdong Wang ◽  
Qi Long ◽  
Yuan Zhang ◽  
Meiling Wang ◽  
...  
Keyword(s):  
Neural Crest ◽  
Signaling Pathway ◽  
Fgf Signaling ◽  
Loss Of Function ◽  
Integrin Activation ◽  
Fgf Receptor ◽  
Adhesion Protein ◽  
Xenopus Embryos ◽  
Focal Adhesion Protein ◽  
The Stability

The focal adhesion protein Kindlin2 is essential for integrin activation, a process that is fundamental to cell-extracellular matrix adhesion. Kindlin2 is widely expressed in mouse embryos, and its absence causes lethality at the peri-implantation stage due to the failure to trigger integrin activation. The function of kindlin2 during embryogenesis has not yet been fully elucidated as a result of this early embryonic lethality. Here, we showed that kindlin2 is essential for neural crest (NC) formation in Xenopus embryos. Loss-of-function assays performed with kindlin2-specific morpholino antisense oligos (MOs) or clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 techniques in Xenopus embryos severely inhibit the specification of NC. Moreover, integrin-binding deficient mutants of Kindlin2 rescued the phenotype caused by loss of kindlin2, suggesting that the function of kindlin2 during NC specification is independent of integrins. Mechanistically, we found that Kindlin2 regulates the fibroblast growth factor (FGF) pathway, and promotes the stability of FGF receptor 1. Our study reveals a novel function of Kindlin2 in regulating FGF signaling pathway and provides mechanistic insights into the function of Kindlin2 during NC specification.

sprouty4 acts in vivo as a feedback-induced antagonist of FGF signaling in zebrafish

Development ◽  
2001 ◽  
Vol 128 (12) ◽  
pp. 2175-2186 ◽  
Author(s):  
Maximilian Fürthauer ◽  
Frank Reifers ◽  
Michael Brand ◽  
Bernard Thisse ◽  
Christine Thisse
Keyword(s):  
Signaling Pathway ◽  
Expression Patterns ◽  
Mitogen Activated Protein Kinase ◽  
Otic Vesicle ◽  
Mesoderm Induction ◽  
Fgf Signaling ◽  
Loss Of Function ◽  
Fgf Receptor ◽  
Mitogen Activated Protein

In looking for novel factors involved in the regulation of the fibroblast growth factor (FGF) signaling pathway, we have isolated a zebrafish sprouty4 gene, based on its extensive similarities with the expression patterns of both fgf8 and fgf3. Through gain- and loss-of-function experiments, we demonstrate that Fgf8 and Fgf3 act in vivo to induce the expression of Spry4, which in turn can inhibit activity of these growth factors. When overexpressed at low doses, Spry4 induces loss of cerebellum and reduction in size of the otic vesicle, thereby mimicking the fgf8/acerebellar mutant phenotype. Injections of high doses of Spry4 cause ventralization of the embryo, an opposite phenotype to the dorsalisation induced by overexpression of Fgf8 or Fgf3. Conversely we have shown that inhibition of Spry4 function through injection of antisense morpholino oligonucleotide leads to a weak dorsalization of the embryo, the phenotype expected for an upregulation of Fgf8 or Fgf3 signaling pathway. Finally, we show that Spry4 interferes with FGF signaling downstream of the FGF receptor 1 (FGFR1). In addition, our analysis reveals that signaling through FGFR1/Ras/mitogen-activated protein kinase pathway is involved, not in mesoderm induction, but in the control of the dorsoventral patterning via the regulation of bone morphogenetic protein (BMP) expression.

scholarly journals Mesoderm induction by activin requires FGF-mediated intracellular signals

Development ◽  
1994 ◽  
Vol 120 (2) ◽  
pp. 463-472 ◽  
Author(s):  
C. LaBonne ◽  
M. Whitman
Keyword(s):  
Plasma Membrane ◽  
Molecular Markers ◽  
Signaling Pathway ◽  
Mesoderm Induction ◽  
Fgf Signaling ◽  
Transcriptional Responses ◽  
Fgf Receptor ◽  
Signal Transducers ◽  
Intracellular Signals

We have examined the role of FGF signaling during activin-mediated mesoderm induction in Xenopus. Using dominant inhibitory mutants of FGF signal transducers to disrupt the FGF-signaling pathway at the plasma membrane or in the cytosol prevents animal cap blastomeres from expressing several mesodermal markers in response to exogenous activin. Dominant inhibitory mutants of the FGF receptor, c-ras or c-raf inhibit the ability of activin to induce molecular markers of both dorsal and ventral mesoderm including Xbra, Mix1 and Xnot. Some transcriptional responses to activin such as goosecoid and Xwnt8 are inhibited less effectively than others, however, suggesting that there may differing requirements for an FGF signal in the responses of mesoderm-specific genes to activin induction. Despite the requirement for this signaling pathway during activin induction, downstream components of this pathway are not activated in response to activin, suggesting that activin does not signal directly through this pathway.

scholarly journals Lacrimo-Auriculo-Dento-Digital Syndrome Is Caused by Reduced Activity of the Fibroblast Growth Factor 10 (FGF10)-FGF Receptor 2 Signaling Pathway

2007 ◽  
Vol 27 (19) ◽  
pp. 6903-6912 ◽  
Author(s):  
Imad Shams ◽  
Edyta Rohmann ◽  
Veraragavan P. Eswarakumar ◽  
Erin D. Lew ◽  
Satoru Yuzawa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Fibroblast Growth Factor ◽  
Signaling Pathway ◽  
Biological Activities ◽  
Fibroblast Growth ◽  
Loss Of Function ◽  
Fgf Receptor ◽  
Fibroblast Growth Factor 10 ◽  
Ladd Syndrome

ABSTRACT Lacrimo-auriculo-dento-digital (LADD) syndrome is characterized by abnormalities in lacrimal and salivary glands, in teeth, and in the distal limbs. Genetic studies have implicated heterozygous mutations in fibroblast growth factor 10 (FGF10) and in FGF receptor 2 (FGFR2) in LADD syndrome. However, it is not clear whether LADD syndrome mutations (LADD mutations) are gain- or loss-of-function mutations. In order to reveal the molecular mechanism underlying LADD syndrome, we have compared the biological properties of FGF10 LADD and FGFR2 LADD mutants to the activities of their normal counterparts. These experiments show that the biological activities of three different FGF10 LADD mutants are severely impaired by different mechanisms. Moreover, haploinsufficiency caused by defective FGF10 mutants leads to LADD syndrome. We also demonstrate that the tyrosine kinase activities of FGFR2 LADD mutants expressed in transfected cells are strongly compromised. Since tyrosine kinase activity is stimulated by ligand-induced receptor dimerization, FGFR2 LADD mutants may also exert a dominant inhibitory effect on signaling via wild-type FGFR2 expressed in the same cell. These experiments underscore the importance of signal strength in mediating biological responses and that relatively small changes in receptor signaling may influence the outcome of developmental processes in cells or organs that do not possess redundant signaling pathway.

scholarly journals FAK and talin: Who is taking whom to the integrin engagement party?

2012 ◽  
Vol 196 (2) ◽  
pp. 185-187 ◽  
Author(s):  
Bryan Serrels ◽  
Margaret C. Frame
Keyword(s):  
Cell Motility ◽  
Focal Adhesion ◽  
Integrin Activation ◽  
Adhesion Protein ◽  
Focal Adhesion Protein ◽  
Protein Recruitment ◽  
The Relationship ◽  
Insight Into

In this issue, Lawson et al. provide new insight into the relationship between FAK and talin during assembly of integrin adhesions on fibronectin. They show that FAK is upstream of talin, and that talin is not required for FAK recruitment or for integrin activation at nascent adhesions. However, FAK-talin binding is required for adhesion turnover and cell motility. The findings question the view that talin is always upstream of focal adhesion protein recruitment to clustered integrin sites.

scholarly journals The focal adhesion protein Testin modulates KCNE2 potassium channel β subunit activity

Channels ◽  
2021 ◽  
Vol 15 (1) ◽  
pp. 229-238
Author(s):  
Maria Papanikolaou ◽  
Shawn M. Crump ◽  
Geoffrey W. Abbott
Keyword(s):  
Potassium Channel ◽  
Focal Adhesion ◽  
Β Subunit ◽  
Adhesion Protein ◽  
Focal Adhesion Protein

scholarly journals The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion

Oncogene ◽  
2021 ◽  
Author(s):  
Qiuping Xu ◽  
Jingwei Zhang ◽  
Brian A. Telfer ◽  
Hao Zhang ◽  
Nisha Ali ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Tumor Growth ◽  
Focal Adhesion ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Adhesion Protein ◽  
Focal Adhesion Protein

AbstractThere is overwhelming clinical evidence that the extracellular-regulated protein kinase 5 (ERK5) is significantly dysregulated in human breast cancer. However, there is no definite understanding of the requirement of ERK5 in tumor growth and metastasis due to very limited characterization of the pathway in disease models. In this study, we report that a high level of ERK5 is a predictive marker of metastatic breast cancer. Mechanistically, our in vitro data revealed that ERK5 was critical for maintaining the invasive capability of triple-negative breast cancer (TNBC) cells through focal adhesion protein kinase (FAK) activation. Specifically, we found that phosphorylation of FAK at Tyr397 was controlled by a kinase-independent function of ERK5. Accordingly, silencing ERK5 in mammary tumor grafts impaired FAK phosphorylation at Tyr397 and suppressed TNBC cell metastasis to the lung without preventing tumor growth. Collectively, these results establish a functional relationship between ERK5 and FAK signaling in promoting malignancy. Thus, targeting the oncogenic ERK5-FAK axis represents a promising therapeutic strategy for breast cancer exhibiting aggressive clinical behavior.

scholarly journals NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1561
Author(s):  
Haitang Yang ◽  
Sean R. R. Hall ◽  
Beibei Sun ◽  
Liang Zhao ◽  
Yanyun Gao ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Checkpoint Inhibitors ◽  
Cancer Cell Line ◽  
Cell Mediated Immunity ◽  
Pleural Mesothelioma ◽  
Precision Oncology ◽  
Hippo Signaling ◽  
Loss Of Function ◽  
Cell Viability Assay ◽  
Molecular Features

(1) Inactivation of the tumor suppressor NF2 is believed to play a major role in the pathogenesis of malignant pleural mesothelioma (MPM) by deregulating the Hippo-YAP signaling pathway. However, NF2 has functions beyond regulation of the Hippo pathway, raising the possibility that NF2 contributes to MPM via Hippo-independent mechanisms. (2) We performed weighted gene co-expression analysis (WGCNA) in transcriptomic and proteomic datasets obtained from The Cancer Gene Atlas (TCGA) MPM cohort to identify clusters of co-expressed genes highly correlated with NF2 and phospho (p)-YAP protein, surrogate markers of active Hippo signaling and YAP inactivation. The potential targets are experimentally validated using a cell viability assay. (3) MPM tumors with NF2 loss-of-function are not associated with changes in p-YAP level nor YAP/TAZ activity score, but are characterized by a deficient B-cell receptor (BCR) signaling pathway. Conversely, MPM tumors with YAP activation display exhausted CD8 T-cell-mediated immunity together with significantly upregulated PD-L1, which is validated in an independent MPM cohort, suggesting a potential benefit of immune-checkpoint inhibitors (ICI) in this patient subset. In support of this, mutations in core Hippo signaling components including LATS2, but not NF2, are independently associated with better overall survival in response to ICI in patients. Additionally, based on cancer cell line models, we show that MPM cells with a high Hippo-YAP activity are particularly sensitive to inhibitors of BCR-ABL/SRC, stratifying a unique MPM patient subset that may benefit from BCR-ABL/SRC therapies. Furthermore, we observe that NF2 physically interacts with a considerable number of proteins that are not involved in the canonical Hippo-YAP pathway, providing a possible explanation for its Hippo-independent role in MPM. Finally, survival analyses show that YAP/TAZ scores together with p-YAP protein level, but not NF2, predict the prognosis of MPM patients. (4) NF2 loss-of-function and dysregulated Hippo-YAP pathway define distinct MPM subsets that differ in their molecular features and prognosis, which has important clinical implications for precision oncology in MPM patients.

scholarly journals GnRH Neuronal Migration and Olfactory Bulb Neurite Outgrowth Are Dependent on FGF Receptor 1 Signaling, Specifically via the PI3K p110α Isoform in Chick Embryo

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 388-399 ◽  
Author(s):  
Youli Hu ◽  
Subathra Poopalasundaram ◽  
Anthony Graham ◽  
Pierre-Marc Bouloux
Keyword(s):  
Chick Embryo ◽  
Olfactory Bulb ◽  
Neurite Outgrowth ◽  
Neuronal Migration ◽  
Glycogen Synthase ◽  
Kallmann Syndrome ◽  
Pi3k Inhibitor ◽  
Fgf Signaling ◽  
In Ovo ◽  
Fgf Receptor

Fibroblast growth factor (FGF) signaling is essential for both olfactory bulb (OB) morphogenesis and the specification, migration, and maturation of the GnRH-secreting neurons. Disruption of FGF signaling contributes to Kallmann syndrome characterized by both anosmia and sexual immaturity. However, several unanswered questions remain as to which specific FGF receptor (FGFR)-1 signaling pathways are necessary for OB and GnRH neuronal development. Here, using pharmacological phosphatidylinositol 3-kinase (PI3K) isoform-specific inhibitors, we demonstrate a central role for the PI3K p110α isoform as a downstream effector of FGFR1 signaling for both GnRH neuronal migration and OB development. We show that signaling via the PI3K p110α isoform is required for GnRH neuronal migration in explant cultures of embryonic day (E) 4 chick olfactory placodes. We also show that in ovo administration of LY294002, a global PI3K inhibitor as well as an inhibitor to the PI3K p110α isoform into the olfactory placode of E3 chick embryo impairs GnRH neuronal migration toward the forebrain. In contrast, in ovo PI3K inhibitor treatment produced no obvious defects on primary olfactory sensory neuron axonal targeting and bundle formation. We also demonstrate that anosmin-1 and FGF2 induced neuronal migration of immortalized human embryonic GnRH neuroblast cells (FNC-B4-hTERT) is mediated by modulating FGFR1 signaling via the PI3K p110α isoform, specifically through phosphorylation of the PI3K downstream effectors, Akt and glycogen synthase kinase-3β. Finally, we show that neurite outgrowth and elongation of OB neurons in E10 chick OB explants are also dependent on the PI3K p110α isoform downstream of FGFR1. This study provides mechanistic insight into the etiology of Kallmann syndrome.

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