Cutting Edge: A Chemical Genetic System for the Analysis of Kinases Regulating T Cell Development

Denzel, Angela; Hare, Katherine J.; Zhang, Chao; Shokat, Kevan M.; Jenkinson, Eric J.; Anderson, Graham; Hayday, Adrian

doi:10.4049/jimmunol.171.2.519

Cited by 24 publications

(13 citation statements)

References 30 publications

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“…This residue is conserved as a large hydrophobic amino acid in the human kinome; a glycine substitution at this site generates an enzyme that uniquely binds unnatural ATP analogs with bulky substitutions (that do not bind any closely related endogenous enzymes). Gatekeeper residue mutations are the basis of the chemical genetic approaches that have been used to engineer kinases that are uniquely sensitive to certain unnatural inhibitor or activator ATP analogs and provide a powerful and elegant strategy to resolve the physiological substrates of individual kinases in cells (42). Moreover, there is growing evidence that the gatekeeper residue also may play a structural role to constrain the flexibility and autocatalytic activation of certain enzymes (53, 179).…”

Section: The Kinase Domainmentioning

confidence: 99%

Structural Basis of Protein Kinase C Isoform Function

Steinberg¹

2008

Physiological Reviews

766

827

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Protein kinase C (PKC) isoforms comprise a family of lipid-activated enzymes that have been implicated in a wide range of cellular functions. PKCs are modular enzymes comprised of a regulatory domain (that contains the membrane-targeting motifs that respond to lipid cofactors, and in the case of some PKCs calcium) and a relatively conserved catalytic domain that binds ATP and substrates. These enzymes are coexpressed and respond to similar stimulatory agonists in many cell types. However, there is growing evidence that individual PKC isoforms subserve unique (and in some cases opposing) functions in cells, at least in part as a result of isoform-specific subcellular compartmentalization patterns, protein-protein interactions, and posttranslational modifications that influence catalytic function. This review focuses on the structural basis for differences in lipid cofactor responsiveness for individual PKC isoforms, the regulatory phosphorylations that control the normal maturation, activation, signaling function, and downregulation of these enzymes, and the intra-/intermolecular interactions that control PKC isoform activation and subcellular targeting in cells. A detailed understanding of the unique molecular features that underlie isoform-specific posttranslational modification patterns, protein-protein interactions, and subcellular targeting (i.e., that impart functional specificity) should provide the basis for the design of novel PKC isoform-specific activator or inhibitor compounds that can achieve therapeutically useful changes in PKC signaling in cells.

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Section: The Kinase Domainmentioning

confidence: 99%

Structural Basis of Protein Kinase C Isoform Function

Steinberg¹

2008

Physiological Reviews

766

827

View full text Add to dashboard Cite

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“…Inhibitor administration suppressed the growth of NIH 3T3 cells expressing a v-erbB inhibitor-sensitive form and not v-erbB WT form in mice injected s.c. with these cells (22). Primary T cells expressing large amounts of an inhibitor sensitive form of LCK were shown to developmentally progress upon drug addition coincident with suppression of kinase activity (23).…”

mentioning

confidence: 99%

Sole BCR-ABL inhibition is insufficient to eliminate all myeloproliferative disorder cell populations

Wong

McLaughlin

Cheng

et al. 2004

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

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Protein kinase inhibitors can be effective in treating selected cancers, but most suppress several kinases. Imatinib mesylate has been useful in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and B cell acute lymphoblastic leukemia through the inhibition of BCR-ABL tyrosine kinase activity. Imatinib mesylate has also been shown to inhibit KIT, ARG, and platelet-derived growth factor receptors ␣ and ␤, and potentially other tyrosine kinases. We have produced a mutant allele of BCR-ABL (T315A) that is uniquely inhibitable by the small molecule 4-amino-1-tert-butyl-3-(1-naphthyl)pyrazolo[3,4-D]pyrimidine and used it to demonstrate that sole suppression of BCR-ABL activity was insufficient to eliminate BCR-ABL ؉ KIT ؉ -expressing immature murine myeloid leukemic cells. In contrast, imatinib mesylate effectively eliminated BCR-ABL ؉ KIT ؉ -expressing leukemic cells. In the cellular context of mature myeloid cells and Pro͞Pre B cells that do not express KIT, monospecific BCR-ABL inhibition was quantitatively as effective as imatinib mesylate in suppressing cell growth and inducing apoptosis. These results suggest that the therapeutic effectiveness of small molecule drugs such as imatinib mesylate could be due to the inhibitor's ability to suppress protein kinases in addition to the dominant target.

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“…This approach is particularly useful for families of highly related kinases, like the SFKs, where developing inhibitors specific for individual family members has been a challenge. Denzel et al describe the selective inhibition of a modified Lck with an analog of PP1 to assess T cell development in fetal thymic organ cultures (40).…”

mentioning

confidence: 99%

The diverse functions of Src family kinases in macrophages

Abram

Lowell²

2008

Front Biosci

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Macrophages are key components of the innate immune response. These cells possess a diverse repertoire of receptors that allow them to respond to a host of external stimuli including cytokines, chemokines, and pathogen-associated molecules. Signals resulting from these stimuli activate a number of macrophage functional responses such as adhesion, migration, phagocytosis, proliferation, survival, cytokine release and production of reactive oxygen and nitrogen species. The cytoplasmic tyrosine kinase Src and its family members (SFKs) have been implicated in many intracellular signaling pathways in macrophages, initiated by a diverse set of receptors ranging from integrins to Toll-like receptors. However, it has been difficult to implicate any given member of the family in any specific pathway. SFKs appear to have overlapping and complementary functions in many pathways. Perhaps the function of these enzymes is to modulate the overall intracellular signaling network in macrophages, rather than operating as exclusive signaling switches for defined pathways. In general, SFKs may function more like rheostats, influencing the amplitude of many pathways. KeywordsTyrosine kinases; signal transduction; innate immunity; integrins; Toll-like receptors; ITIM; ITAM; adhesion; migration; Hck; Fgr; Lyn; Review INTRODUCTION Src family kinases -general approachesc-Src was first described as the cellular counterpart of v-Src, the transforming gene found in Rous Sarcoma Virus, and has since been the focus of much research. Src and its other family members, referred to as Src Family Kinases (SFKs) throughout this review, have been implicated in many diverse signaling pathways in both immune (1) and non-immune cell types (2). This is apparent from the close to 25,000 PubMed hits one gets when researching these enzymes. Furthermore, a strong clinical interest has developed in SFKs based on the growing realization of their central roles in human cancer (3, 4).Src family members include c-Src, Fyn, c-Yes, Lck, Hck, c-Fgr, Lyn, Blk, and Yrk. Src, Fyn and Yes are ubiquitously expressed whereas Lck, Hck, Fgr, Lyn and Blk tend to be more restricted to cells of hematopoietic origin. Yrk has only been found in chickens. The SFKs Send correspondence to: Dr Clifford Lowell, Department of Laboratory Medicine, University of California, San Francisco, S1058, 513 Parnassus Avenue, San Francisco, CA94143-0451, Tel: 415-476-2540, Fax: 415-502-9404, clifford.lowell@ucsf.edu. HHS Public AccessAuthor manuscript Front Biosci. Author manuscript; available in PMC 2015 June 05. Published in final edited form as:Front Biosci. ; 13: 4426-4450. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript are cytoplasmic tyrosine kinases, consisting of an N-terminal unique domain, a Src homology 3 (SH3) domain that can interact with polyproline-rich motifs, a Src homology 2 (SH2) domain that binds phosphotyrosine residues, and a tyrosine kinase domain ( Figure 1A). Acylation of SFKs at their N-terminus (palmitoylation and/or myristoylation) al...

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Cutting Edge: A Chemical Genetic System for the Analysis of Kinases Regulating T Cell Development

Cited by 24 publications

References 30 publications

Structural Basis of Protein Kinase C Isoform Function

Structural Basis of Protein Kinase C Isoform Function

Sole BCR-ABL inhibition is insufficient to eliminate all myeloproliferative disorder cell populations

The diverse functions of Src family kinases in macrophages

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