Seminars in Cell & Developmental Biology 37 (2015) 56–57
Contents lists available at ScienceDirect
Seminars in Cell & Developmental Biology journal homepage: www.elsevier.com/locate/semcdb
Editorial
Protein tyrosine phosphatases
It probably is impossible to overstate the importance of tyrosine phosphorylation in the development and function of metazoan tissues. The intricacies of the processes mediated by this post-translational modification at an organismal level mirror the complex regulatory mechanisms controlling the enzymatic activities of tyrosine kinases and phosphatases. In this special issue of Seminars in Cell and Developmental Biology, eight laboratories have combined forces to provide us with up-to-date reviews on specific protein tyrosine phosphatases (PTPs) or PTP families. Taken together, these reviews highlight the great diversity and even greater complexity of the physiological processes in which these enzymes are involved in as well as the signaling mechanisms underlying these functions. The issue starts with a contribution from the Haj lab focused on the “original” PTP, PTP1B [1], and the multiple roles it plays in metabolic disorders. In particular, the authors highlight the functions of PTP1B in leptin and insulin signaling. They also address the recent identification of the M2 form of pyruvate kinase as a PTP1B substrate, which suggests a role in regulating energy balance. One of the techniques that led to breakthroughs in our understanding of PTP1B biology involves engineering its catalytic site to impair activity thus transforming PTP1B into a substrate trap to isolate targets. Anton Bennett and colleagues expand on the use of unbiased proteomic techniques to identify PTP substrates. They also present genomic strategies involving shRNA and siRNA screening to uncover new PTP functions. Finally, drawing on their own extensive experience, the authors explain how they used a phosphotyrosyl peptide enhancement strategy to identify targets of the phosphatase SHP2 in a mouse model of Noonan syndrome, a genetic disorder characterized by mutations in SHP2 that leads congenital heart defects, among other anomalies. Maria Kontaridis and colleagues examine the role of SHP2 in cardiac development in further detail. In this comprehensive paper, the authors provide an overview of the signaling mechanism of SHP2 and explain how mutations found in Leopard and Noonan syndromes affect the catalytic properties of SHP2. They then highlight the role played by SHP2 in shaping heart tissues at multiple stages, from early in development to the maturation of cardiac chambers. Interestingly, they indicate that many of the SHP2 targets during these events remain elusive, further highlighting the need of unbiased proteomic approaches such as the ones summarized by Anton Bennett and colleagues. Finally, the role of SHP2, and indeed additional PTPs, in the regulation of stem cell homeostasis is the focus of the paper by Dubreuil, Sap and Harroch. Extending
http://dx.doi.org/10.1016/j.semcdb.2015.01.004 1084-9521/© 2015 Published by Elsevier Ltd.
beyond non-receptor PTPs, the authors also highlight the specific roles played by receptor PTPs (RPTPs) in stem cell biology with a particular emphasis on cells in the oligodendrocyte lineage. One of the first confirmations that RPTPs might play critical roles in the development of the nervous system came from experiments demonstrating that mutations of the RPTPs Dlar, DPTP69D and DPTP99A led to motor axon guidance defects in Drosophila [2,3]. These results led many excellent labs to focus on the functions played by RPTPs in the nervous system. In this issue, Andrew Stoker provides us with an overview of the recent findings in that research area. In particular, he highlights the exciting roles that type IIA RPTPs (LAR, RPTP␦ and RPTP in vertebrates, Dlar in Drosophila) play in nerve regeneration and synapse formation. He also addresses results from RPTP knockout mice indicating that RPTPs might be linked to neuropsychiatric disorders, possibly opening the door for the design of RPTP-based therapies for these conditions. With that in mind, Radu Aricescu, Charlotte Coles, Yvonne Jones, who together pioneered the structural characterization of RPTP ectodomains [4,5], cover the latest structural results obtained for type IIA RPTPs. In particular, they provide a molecular understanding of how these receptors associate with multiple ligands during axon guidance and synaptogenesis and explain how ligands might compete for binding sites on these molecules. Thus, the authors highlight an unexpected level of complexity in RPTPs, as these receptors integrate distinct extracellular cues during development. It remains unclear as to whether all RPTPs behave in similar fashion, but it is now critical to investigate the matter further. The strong expression of RPTPs in the nervous system has been leveraged to develop novel tools for cancer detection. Indeed, in their review about the roles of the type IIB family of RPTPs, Sonya Craig and Susann Brady-Kalnay show how they can utilize the shedding of the ectodomain of the phosphatase RPTP occurring in glioma cells to develop imaging probes to monitor tumor growth and facilitate the surgical removal of cancerous tissues. Extending beyond the nervous system, Craig and Brady-Kalnay also examine the functions of the four type IIB RPTPs in development. Finally, Mili Jeon and Kai Zinn share their insights into the roles of type III RPTPs in the development of metazoan tissues. These receptors stand in contrast from the type IIA and type IIB RPTPs, as many of their extracellular binding partners remain to be identified. However, the functions played by these molecules have been characterized in more detail. Indeed, using examples from C. elegans, Drosophila, and mouse, Jeon and Zinn describe how these RPTPs
Editorial / Seminars in Cell & Developmental Biology 37 (2015) 56–57
balance the activities of receptor tyrosine kinases. Furthermore, the authors address how type III RPTPs play conserved roles in the development of tubular organs in invertebrates and vertebrates. Taken together, these eight reviews emphasize how far the field of PTP biology has progressed in a very short amount of time. To be sure, much remains to be learned about the substrates and binding partners of PTPs and how these proteins participate in metazoan development, but there is a sense that the necessary discovery tools are available. Thus, one might reasonably ask what the next frontier in PTP research is? Perhaps the most exciting prospect is the design of PTP-based therapeutic strategies to combat cancers or treat neuropsychiatric disorders. Stay tuned. References [1] Tonks NK, Diltz CD, Fischer EH. Purification of the major protein-tyrosinephosphatases of human placenta. J Biol Chem 1988;263:6722–30.
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[2] Desai CJ, Gindhart JG, Goldstein LS, Zinn K. Receptor tyrosine phosphatases are required for motor axon guidance in the Drosophila embryo. Cell 1996;84:599–609. [3] Krueger NX, Van Vactor D, Wan HI, Gelbart WM, Goodman CS, Saito H. The transmembrane tyrosine phosphatase DLAR controls motor axon guidance in Drosophila. Cell 1996;84:611–22. [4] Aricescu AR, Siebold C, Choudhuri K, Chang VT, Lu W, Davis SJ, et al. Structure of a tyrosine phosphatase adhesive interaction reveals a spacer-clamp mechanism. Science 2007;317:1217–20. [5] Coles CH, Shen Y, Tenney AP, Siebold C, Sutton GC, Lu W, et al. Proteoglycanspecific molecular switch for RPTP clustering and neuronal extension. Science 2011;332:484–8.
Samuel Bouyain E-mail address: [email protected]
Contents lists available at ScienceDirect
Seminars in Cell & Developmental Biology journal homepage: www.elsevier.com/locate/semcdb
Editorial
Protein tyrosine phosphatases
It probably is impossible to overstate the importance of tyrosine phosphorylation in the development and function of metazoan tissues. The intricacies of the processes mediated by this post-translational modification at an organismal level mirror the complex regulatory mechanisms controlling the enzymatic activities of tyrosine kinases and phosphatases. In this special issue of Seminars in Cell and Developmental Biology, eight laboratories have combined forces to provide us with up-to-date reviews on specific protein tyrosine phosphatases (PTPs) or PTP families. Taken together, these reviews highlight the great diversity and even greater complexity of the physiological processes in which these enzymes are involved in as well as the signaling mechanisms underlying these functions. The issue starts with a contribution from the Haj lab focused on the “original” PTP, PTP1B [1], and the multiple roles it plays in metabolic disorders. In particular, the authors highlight the functions of PTP1B in leptin and insulin signaling. They also address the recent identification of the M2 form of pyruvate kinase as a PTP1B substrate, which suggests a role in regulating energy balance. One of the techniques that led to breakthroughs in our understanding of PTP1B biology involves engineering its catalytic site to impair activity thus transforming PTP1B into a substrate trap to isolate targets. Anton Bennett and colleagues expand on the use of unbiased proteomic techniques to identify PTP substrates. They also present genomic strategies involving shRNA and siRNA screening to uncover new PTP functions. Finally, drawing on their own extensive experience, the authors explain how they used a phosphotyrosyl peptide enhancement strategy to identify targets of the phosphatase SHP2 in a mouse model of Noonan syndrome, a genetic disorder characterized by mutations in SHP2 that leads congenital heart defects, among other anomalies. Maria Kontaridis and colleagues examine the role of SHP2 in cardiac development in further detail. In this comprehensive paper, the authors provide an overview of the signaling mechanism of SHP2 and explain how mutations found in Leopard and Noonan syndromes affect the catalytic properties of SHP2. They then highlight the role played by SHP2 in shaping heart tissues at multiple stages, from early in development to the maturation of cardiac chambers. Interestingly, they indicate that many of the SHP2 targets during these events remain elusive, further highlighting the need of unbiased proteomic approaches such as the ones summarized by Anton Bennett and colleagues. Finally, the role of SHP2, and indeed additional PTPs, in the regulation of stem cell homeostasis is the focus of the paper by Dubreuil, Sap and Harroch. Extending
http://dx.doi.org/10.1016/j.semcdb.2015.01.004 1084-9521/© 2015 Published by Elsevier Ltd.
beyond non-receptor PTPs, the authors also highlight the specific roles played by receptor PTPs (RPTPs) in stem cell biology with a particular emphasis on cells in the oligodendrocyte lineage. One of the first confirmations that RPTPs might play critical roles in the development of the nervous system came from experiments demonstrating that mutations of the RPTPs Dlar, DPTP69D and DPTP99A led to motor axon guidance defects in Drosophila [2,3]. These results led many excellent labs to focus on the functions played by RPTPs in the nervous system. In this issue, Andrew Stoker provides us with an overview of the recent findings in that research area. In particular, he highlights the exciting roles that type IIA RPTPs (LAR, RPTP␦ and RPTP in vertebrates, Dlar in Drosophila) play in nerve regeneration and synapse formation. He also addresses results from RPTP knockout mice indicating that RPTPs might be linked to neuropsychiatric disorders, possibly opening the door for the design of RPTP-based therapies for these conditions. With that in mind, Radu Aricescu, Charlotte Coles, Yvonne Jones, who together pioneered the structural characterization of RPTP ectodomains [4,5], cover the latest structural results obtained for type IIA RPTPs. In particular, they provide a molecular understanding of how these receptors associate with multiple ligands during axon guidance and synaptogenesis and explain how ligands might compete for binding sites on these molecules. Thus, the authors highlight an unexpected level of complexity in RPTPs, as these receptors integrate distinct extracellular cues during development. It remains unclear as to whether all RPTPs behave in similar fashion, but it is now critical to investigate the matter further. The strong expression of RPTPs in the nervous system has been leveraged to develop novel tools for cancer detection. Indeed, in their review about the roles of the type IIB family of RPTPs, Sonya Craig and Susann Brady-Kalnay show how they can utilize the shedding of the ectodomain of the phosphatase RPTP occurring in glioma cells to develop imaging probes to monitor tumor growth and facilitate the surgical removal of cancerous tissues. Extending beyond the nervous system, Craig and Brady-Kalnay also examine the functions of the four type IIB RPTPs in development. Finally, Mili Jeon and Kai Zinn share their insights into the roles of type III RPTPs in the development of metazoan tissues. These receptors stand in contrast from the type IIA and type IIB RPTPs, as many of their extracellular binding partners remain to be identified. However, the functions played by these molecules have been characterized in more detail. Indeed, using examples from C. elegans, Drosophila, and mouse, Jeon and Zinn describe how these RPTPs
Editorial / Seminars in Cell & Developmental Biology 37 (2015) 56–57
balance the activities of receptor tyrosine kinases. Furthermore, the authors address how type III RPTPs play conserved roles in the development of tubular organs in invertebrates and vertebrates. Taken together, these eight reviews emphasize how far the field of PTP biology has progressed in a very short amount of time. To be sure, much remains to be learned about the substrates and binding partners of PTPs and how these proteins participate in metazoan development, but there is a sense that the necessary discovery tools are available. Thus, one might reasonably ask what the next frontier in PTP research is? Perhaps the most exciting prospect is the design of PTP-based therapeutic strategies to combat cancers or treat neuropsychiatric disorders. Stay tuned. References [1] Tonks NK, Diltz CD, Fischer EH. Purification of the major protein-tyrosinephosphatases of human placenta. J Biol Chem 1988;263:6722–30.
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[2] Desai CJ, Gindhart JG, Goldstein LS, Zinn K. Receptor tyrosine phosphatases are required for motor axon guidance in the Drosophila embryo. Cell 1996;84:599–609. [3] Krueger NX, Van Vactor D, Wan HI, Gelbart WM, Goodman CS, Saito H. The transmembrane tyrosine phosphatase DLAR controls motor axon guidance in Drosophila. Cell 1996;84:611–22. [4] Aricescu AR, Siebold C, Choudhuri K, Chang VT, Lu W, Davis SJ, et al. Structure of a tyrosine phosphatase adhesive interaction reveals a spacer-clamp mechanism. Science 2007;317:1217–20. [5] Coles CH, Shen Y, Tenney AP, Siebold C, Sutton GC, Lu W, et al. Proteoglycanspecific molecular switch for RPTP clustering and neuronal extension. Science 2011;332:484–8.
Samuel Bouyain E-mail address: [email protected]
