Phosphoproteomic analysis identifies insulin enhancement of discoidin domain receptor 2 phosphorylation

Iwai, Leo Kei; Chang, Fumin; Huang, Paul H.

doi:10.4161/cam.22572

Cited by 25 publications

(15 citation statements)

References 24 publications

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“…Indeed, DDRs bind to multiple collagens and both exhibit unique and common structural and activation properties, but phosphorylate different target receptors (Ongusaha et al, 2003 ). In addition, DDRs may act in concert with other signaling receptors, including the Wnt5a/Frizzled (Dejmek et al, 2003 ) and Notch1 (Kim et al, 2011 ) receptors in the case of DDR1 and the insulin receptor (Iwai et al, 2013a ) in the case of DDR2. Finally, DDRs signaling is cell/tissue type-specific and context-dependent.…”

Section: Structure Function and Regulation Of Ddrs (Figure mentioning

confidence: 99%

Discoidin Domain Receptors: Potential Actors and Targets in Cancer

Rammal

Saby²,

Magnien³

et al. 2016

Front. Pharmacol.

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The extracellular matrix critically controls cancer cell behavior by inducing several signaling pathways through cell membrane receptors. Besides conferring structural properties to tissues around the tumor, the extracellular matrix is able to regulate cell proliferation, survival, migration, and invasion. Among these receptors, the integrins family constitutes a major class of receptors that mediate cell interactions with extracellular matrix components. Twenty years ago, a new class of extracellular matrix receptors has been discovered. These tyrosine kinase receptors are the two discoidin domain receptors DDR1 and DDR2. DDR1 was first identified in the Dictyostelium discoideum and was shown to mediate cell aggregation. DDR2 shares highly conserved sequences with DDR1. Both receptors are activated upon binding to collagen, one of the most abundant proteins in extracellular matrix. While DDR2 can only be activated by fibrillar collagen, particularly types I and III, DDR1 is mostly activated by type I and IV collagens. In contrast with classical growth factor tyrosine kinase receptors which display a rapid and transient activation, DDR1 and DDR2 are unique in that they exhibit delayed and sustained receptor phosphorylation upon binding to collagen. Recent studies have reported differential expression and mutations of DDR1 and DDR2 in several cancer types and indicate clearly that these receptors have to be taken into account as new players in the different aspects of tumor progression, from non-malignant to highly malignant and invasive stages. This review will discuss the current knowledge on the role of DDR1 and DDR2 in malignant transformation, cell proliferation, epithelial to mesenchymal transition, migratory, and invasive processes, and finally the modulation of the response to chemotherapy. These new insights suggest that DDR1 and DDR2 are new potential targets in cancer therapy.

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Section: Structure Function and Regulation Of Ddrs (Figure mentioning

confidence: 99%

Discoidin Domain Receptors: Potential Actors and Targets in Cancer

Rammal

Saby²,

Magnien³

et al. 2016

Front. Pharmacol.

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“…In this way, different receptor systems cooperate to effect a particular signalling outcome. While little evidence exists for cooperation of DDRs with other RTKs, a recent phosphoproteomic study showed that the insulin signalling pathway promotes collagen-induced DDR2 phosphorylation (Iwai et al, 2013a); the mechanism by which this is achieved has not been explored. In this context it is also interesting that the RTK EphA2 was co-immunoprecipitated with pervanadate-activated DDR1 (Lemeer et al, 2012).…”

Section: Signalling By Ddrsmentioning

confidence: 99%

Discoidin Domain Receptor Functions in Physiological and Pathological Conditions

Leitinger

2014

International Review of Cell and Molecular Biology

305

362

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The discoidin domain receptors, DDR1 and DDR2, are non-integrin collagen receptors that are members of the receptor tyrosine kinase family. Both DDRs bind a number of different collagen types and play important roles in embryo development. Dysregulated DDR function is associated with progression of various human diseases, including fibrosis, arthritis and cancer. By interacting with key components of the extracellular matrix and displaying distinct activation kinetics, the DDRs form a unique subfamily of receptor tyrosine kinases. DDR-facilitated cellular functions include cell migration, cell survival, proliferation and differentiation, as well as remodelling of extracellular matrices. This review summarises the current knowledge of DDR-ligand interactions, DDR-initiated signal pathways and the molecular mechanisms that regulate receptor function. Also discussed are the roles of DDRs in development and disease progression.

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“…Stimulation of cells with collagen I and insulin promotes Tyr740 as well as total tyrosine phosphorylation of DDR2 receptor to a greater extent than the phosphorylation stimulated by collagen I alone (Iwai et al, 2013a). Finally, it has been proposed that collagen-stimulated DDR1 promotes survival of cancer cells by binding to and activating Notch1 thus promoting the activation of the two transcription factors Hes1 and Hey2 (Kim et al, 2011).…”

Section: Ddrs Cross-talk With Receptors and Growth Factorsmentioning

confidence: 99%

Discoidin domain receptors in disease

2014

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Discoidin domain receptors, DDR1 and DDR2, lie at the intersection of two large receptor families, namely the extracellular matrix and tyrosine kinase receptors. As such, DDRs are uniquely positioned to function as sensors for extracellular matrix and to regulate a wide range of cell functions from migration and proliferation to cytokine secretion and extracellular matrix homeostasis/remodeling. While activation of DDRs by extracellular matrix collagens is required for normal development and tissue homeostasis, aberrant activation of these receptors following injury or in disease is detrimental. The availability of mice lacking DDRs has enabled us to identify key roles played by these receptors in disease initiation and progression. DDR1 promotes inflammation in atherosclerosis, lung fibrosis and kidney injury, while DDR2 contributes to osteoarthritis. Furthermore, both DDRs have been implicated in cancer progression. Yet the mechanisms whereby DDRs contribute to diseases progression are poorly understood. In this review we highlight the mechanisms whereby DDRs regulate two important processes, namely inflammation and tissue fibrosis. In addition, we discuss the challenges of targeting DDRs in disease. Selective targeting of these receptors requires understanding of how they interact with and are activated by extracellular matrix, and whether their cellular function is dependent on or independent of receptor kinase activity.

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Phosphoproteomic analysis identifies insulin enhancement of discoidin domain receptor 2 phosphorylation

Cited by 25 publications

References 24 publications

Discoidin Domain Receptors: Potential Actors and Targets in Cancer

Discoidin Domain Receptors: Potential Actors and Targets in Cancer

Discoidin Domain Receptor Functions in Physiological and Pathological Conditions

Discoidin domain receptors in disease

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