Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration

Okigaki, Mitsuhiko; Davis, Caitlin; Falasca, Marco; Harroch, Sheila; Felsenfeld, Dan P.; Sheetz, Michael P.; Schlessinger, Joseph

doi:10.1073/pnas.1834348100

Cited by 271 publications

(308 citation statements)

References 40 publications

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“…Pyk2 is enriched in adult neurons and plays an important role in neuronal plasticity [2][3][4][5][6]. In non-neuronal cells, Pyk2 is involved in osteoclast function [7], macrophage migration [8], and focal adhesion disassembly [9]. Neuronal Pyk2 is 5 kDa larger than in cells from the hematopoietic lineage, due to the retention of an additional exon coding for a peptide between the kinase and focal adhesion targeting (FAT) domains [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

Faure

Ramos

Girault

2012

Cell. Mol. Life Sci.

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Cytonuclear signaling is essential for long-term alterations of cellular properties. Several pathways involving regulated nuclear accumulation of Ser/Thr kinases have been described but little is known about cytonuclear trafficking of tyrosine kinases. Proline-rich tyrosine kinase 2 (Pyk2) is a cytoplasmic non-receptor tyrosine kinase enriched in neurons and involved in functions ranging from synaptic plasticity to bone resorption, as well as in cancer. We previously showed the Ca 2? -induced, calcineurin-dependent, nuclear localization of Pyk2. Here, we characterize the molecular mechanisms of Pyk2 cytonuclear localization in transfected PC12 cells. The 700-841 linker region of Pyk2 recapitulates its depolarizationinduced nuclear accumulation. This region includes a nuclear export motif regulated by phosphorylation at residue S778, a substrate of cAMP-dependent protein kinase and calcineurin. Nuclear import is controlled by a previously identified sequence in the N-terminal domain and by a novel nuclear targeting signal in the linker region. Regulation of cytonuclear trafficking is independent of Pyk2 activity. The region regulating nuclear localization is absent from the non-neuronal shorter splice isoform of Pyk2. Our results elucidate the mechanisms of Ca 2? -induced nuclear accumulation of Pyk2. They also suggest that Pyk2 nuclear accumulation is a novel type of signaling response that may contribute to specific long-term adaptations in neurons.

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Section: Introductionmentioning

confidence: 99%

Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

Faure

Ramos

Girault

2012

Cell. Mol. Life Sci.

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“…Pyk2 knock-out mice are viable and fertile (49), whereas knocking out FAK results in embryonic lethality (50), suggesting the selective inhibition of Pyk2 may have therapeutic advantages. In this regard it is notable that recently inhibitors with strong selectivity for Pyk2 over FAK have been identified (51).…”

Section: Discussionmentioning

confidence: 99%

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

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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 ...

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“…PYK2 (proline-rich tyrosine kinase 2, also known as RAFTK, CADTK or CAKb), the second member of the focal adhesion kinase family, regulates focal adhesion turnover (Avraham et al, 2000;Gelman, 2003) and cell motility (Sieg et al, 1998;Guinamard et al, 2000;Ivankovic-Dikic et al, 2000;Okigaki et al, 2003); therefore, we studied the role of PYK2 in cell-cell repulsion. We found that PYK2 localizes at focal adhesions and promotes cell-cell repulsion.…”

Section: Introductionmentioning

confidence: 99%

Ca²⁺ lightning conveys cell–cell contact information inside the cells

et al. 2006

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Cells communicate with each other to form organized structures by cell-cell adhesion and cell-cell repulsion, but it remains to be clarified how cell-cell contact information is converted into intracellular signals. Here, we show that cells in contact with neighbouring cells generate local transient intracellular Ca 2 þ signals (Ca 2 þ lightning). Ca 2 þ lightning was observed near cellcell contact regions and was not observed in the central regions of cells or in solitary cells that were not in contact with other cells. We also show that Ca 2 þ lightning is able to regulate cellcell repulsion by means of PYK2, a Ca 2 þ -activated protein tyrosine kinase, which induces focal adhesion disassembly in a Ca 2 þ -dependent manner. These results show that cell-cell contact information might be transmitted by Ca 2 þ lightning to regulate intracellular events.

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Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration

Cited by 271 publications

References 40 publications

Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

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

Ca²⁺ lightning conveys cell–cell contact information inside the cells

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Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration

Cited by 271 publications

References 40 publications

Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

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

Ca2+ lightning conveys cell–cell contact information inside the cells

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Ca²⁺ lightning conveys cell–cell contact information inside the cells