Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

Faure, Camille; Ramos, Mariana Gontijo; Girault, Jean‐Antoine

doi:10.1007/s00018-012-1075-5

Cited by 22 publications

(28 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Faure et al (48) mapped several activities such as nuclear accumulation of Pyk2 to the same region we identified. However, they found serine phosphorylation in the alternatively spliced region played a role (48). Thus in their studies, the shorter isoform of Pyk2 lacked the activities, whereas we found the shorter isoform of Pyk2 still interacts with Shc1.…”

Section: Discussioncontrasting

confidence: 47%

Up-regulation of N-cadherin by Collagen I-activated Discoidin Domain Receptor 1 in Pancreatic Cancer Requires the Adaptor Molecule Shc1

Huang¹,

Svoboda²,

Lazenby³

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinomas are highly malignant cancers characterized by extensive invasion into surrounding tissues, metastasis to distant organs, and a limited response to therapy. A main feature of pancreatic ductal adenocarcinomas is desmoplasia, which leads to extensive deposition of collagen I. We have demonstrated that collagen I can induce epithelialmesenchymal transition (EMT) in pancreatic cancer cells. A hallmark of EMT is an increase in the expression of the mesenchymal cadherin N-cadherin. Previously we showed up-regulation of N-cadherin promotes tumor cell invasion and that collagen I-induced EMT is mediated by two collagen receptors, ␣2␤1-integrin and discoidin domain receptor 1 (DDR1). DDR1 is a receptor-tyrosine kinase widely expressed during embryonic development and in many adult tissues and is also highly expressed in many different cancers. In the signaling pathway initiated by collagen, we have shown proline-rich tyrosine kinase 2 (Pyk2) is downstream of DDR1. In this study we found isoform b of DDR1 is responsible for collagen I-induced up-regulation of N-cadherin and tyrosine 513 of DDR1b is necessary. Knocking down Shc1, which binds to tyrosine 513 of DDR1b via its PTB (phosphotyrosine binding) domain, eliminates the upregulation of N-cadherin. The signaling does not require a functional SH2 domain or the tyrosine residues commonly phosphorylated in Shc1 but is mediated by the interaction between a short segment of the central domain of Shc1 and the proline-rich region of Pyk2. Taken together, these data illustrate DDR1b, but not DDR1a, mediates collagen I-induced N-cadherin up-regulation, and Shc1 is involved in this process by coupling to both DDR1 and Pyk2.Pancreatic cancer is currently the fourth leading cause of cancer-related mortality in the United States with a 5-year survival rate of ϳ6% (American Cancer Society, 2014). This unfortunate outcome is mainly due to the aggressive behavior of this cancer and the lack of symptoms early in the disease. One of the major features of pancreatic cancer is that during the early stages an extensive stromal reaction occurs called desmoplasia. A dense stroma forms, which consists of myofibroblasts (pancreatic stellate cells), abundant extracellular matrix, and different types of inflammatory cells including macrophages, mast cells, lymphocytes, and plasma cells (1, 2). The extracellular matrix components include collagens, fibronectin, hyaluronic acid, and proteoglycans, whereas the major part is type I collagen (3, 4).The atypical stroma plays many roles in pancreatic cancer. It changes the normal architecture of pancreatic tissue and induces an abnormal configuration of blood and lymphatic vessels resulting in a hypovascular and hypoxic microenvironment. It also presents a barrier to drug delivery and promotes tumor immunologic tolerance (2, 4). Previously, our laboratory showed that collagen I can induce epithelial-mesenchymal transition (EMT) 2 -like changes in pancreatic cancer mediated by two collagen receptors, ␣2␤1-integrin and ...

show abstract

Section: Discussioncontrasting

confidence: 47%

Up-regulation of N-cadherin by Collagen I-activated Discoidin Domain Receptor 1 in Pancreatic Cancer Requires the Adaptor Molecule Shc1

Huang¹,

Svoboda²,

Lazenby³

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Subcellular redistribution of phospho-Y402 Pyk2 represents a previously unidentified mechanism of modulating the profile of substrates phosphorylated by Pyk2 and possibly associated Src kinases. Accumulation of Pyk2 and phospho-Y402 Pyk2 in proximal dendrites, somata, and intranuclear compartments of rat hippocampal slices has been observed after depolarization in vitro (22,37).…”

Section: Discussionmentioning

confidence: 95%

Role for NUP62 depletion and PYK2 redistribution in dendritic retraction resulting from chronic stress

Kinoshita¹,

Hunter

Gray

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Genetic evidence suggests cell-type-specific functions for certain nucleoporins, and gene expression profiling has revealed that nucleoporin p62 (NUP62) transcripts are decreased in the prefrontal cortex of major depressives. Chronic stress, which can precipitate depression, induces changes in the architecture and plasticity of apical dendrites that are particularly evident in the CA3 region of the hippocampus. Genetically targeted translating ribosome affinity purification revealed a selective reduction in translated Nup62 transcripts in CA3 of chronically stressed mice, and the Nup62 protein content of nuclei extracted from whole hippocampus was found to be decreased in chronically stressed rats. In cultured cells, phosphorylation of a FAK/proline-rich tyrosine kinase 2 (PYK2) consensus site in the alpha-helical domain of NUP62 (human Y422) is shown to be associated with shedding of NUP62 from the nuclear pore complex (NPC) and/or retention of NUP62 in the cytoplasm. Increased levels of phospho-Y425 Nup62 were observed in cytoplasmic fractions of hippocampi from chronically stressed rats, and immunofluorescence microscopy revealed redistribution of activated Pyk2 to the perinuclear region of stressed pyramidal neurons. Depletion of Nup62 from cultured embryonic day 18 rat hippocampal and cortical neurons resulted in simplification and retraction of dendritic arbors, without disruption of axon initial segment integrity. Thus, at least two types of mechanisms-one affecting expression and the other association with the NPC-could contribute to loss of NUP62 from CA3 pyramidal neurons during chronic stress. Their combined actions may account for the enhanced responsiveness of CA3 apical dendrites to chronic stress and may either be pathogenic or serve to protect CA3 neurons from permanent damage.nucleoporin p62 | proline-rich tyrosine kinase 2 | chronic stress | dendrite retraction | hippocampus S ubstructures of the nuclear pore complex (NPC) are visible by electron microscopy and include an inner scaffold that interfaces the nuclear envelope, a central channel, and two asymmetric rings that project into either the cytoplasm or the nucleus (1). Selective nucleocytoplasmic transport through the NPC is mediated by phenylalanine-glycine (FG)-repeat-containing nucleoporins in the central channel and asymmetric ring structures. Some FG-repeat nucleoporins, including the central channel nucleoporin p62 (NUP62), function in transcription and chromatin organization independently of their roles in transport (2-4). Tissue-specific genetic diseases arising from mutations in nucleoporins have suggested that the NPC and/or its components can mediate celltype-specific functions (5, 6). For example, the Q391P mutation in NUP62 causes autosomal recessive infantile bilateral striatal necrosis (IBSN), a fatal degeneration of the corpus striatum that occurs during early childhood (7). Although Nup62 null mice are embryonic day 7 lethal (8), human Q391P homozygotes develop past term, suggesting that the mutation affects a specialized...

show abstract

“…Pyk2 accumulates in the nucleus following Ca 2þ influx (Faure et al, 2007), suggesting a correlation between Ca 2þ /CaMbinding and nuclear localisation. This translocation involves dephosphorylation of S778 by calcineurin, a Ca 2þ /CaM activated phosphatase, which appears to inactivate a nuclear export sequence (Faure et al, 2013).…”

Section: Nuclear Pyk2mentioning

confidence: 99%

How to awaken your nanomachines: Site-specific activation of focal adhesion kinases through ligand interactions

Walkiewicz

Girault

Arold

2015

Progress in Biophysics and Molecular Biology

Self Cite

View full text Add to dashboard Cite

The focal adhesion kinase (FAK) and the related protein-tyrosine kinase 2-beta (Pyk2) are highly versatile multidomain scaffolds central to cell adhesion, migration, and survival. Due to their key role in cancer metastasis, understanding and inhibiting their functions are important for the development of targeted therapy. Because FAK and Pyk2 are involved in many different cellular functions, designing drugs with partial and function-specific inhibitory effects would be desirable. Here, we summarise recent progress in understanding the structural mechanism of how the tug-of-war between intramolecular and intermolecular interactions allows these protein 'nanomachines' to become activated in a site-specific manner.

show abstract

Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

Cited by 22 publications

References 55 publications

Up-regulation of N-cadherin by Collagen I-activated Discoidin Domain Receptor 1 in Pancreatic Cancer Requires the Adaptor Molecule Shc1

Up-regulation of N-cadherin by Collagen I-activated Discoidin Domain Receptor 1 in Pancreatic Cancer Requires the Adaptor Molecule Shc1

Role for NUP62 depletion and PYK2 redistribution in dendritic retraction resulting from chronic stress

How to awaken your nanomachines: Site-specific activation of focal adhesion kinases through ligand interactions

Contact Info

Product

Resources

About