Regulatory roles of conserved phosphorylation sites in the activation T-loop of the MAP kinase ERK1

Lai, Shenshen; Pelech, Steven

doi:10.1091/mbc.e15-07-0527

Cited by 31 publications

(33 citation statements)

References 79 publications

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“…IKKβ and PKCδ are also phosphorylated at the equivalent Tyr residue by Src and in H 2 O 2 treated cells, respectively 52, 53 . Interestingly, in the Extracellular Signal-Regulated Kinase 1 (ERK1), phosphorylation of either T207 ERK1 (201 PKA ) or Y210 ERK1 (204 PKA ) reduces kinase activity 54 . The preponderance of T201 PKA and Y204 PKA phosphorylation in STKs and the observed divergence in PTKs (where the Tyr is replaced by non-phosphorylatable hydrophobic residues) suggest that regulation by modification of P+1 pocket residues is a selective feature of STKs.…”

Section: Resultsmentioning

confidence: 99%

KinView: a visual comparative sequence analysis tool for integrated kinome research

et al. 2016

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Multiple sequence alignments (MSAs) are a fundamental analysis tool used throughout biology to investigate relationships between protein sequence, structure, function, evolutionary history, and patterns of disease-associated variants. However, their widespread application in systems biology research is currently hindered by the lack of user-friendly tools to simultaneously visualize, manipulate and query the information conceptualized in large sequence alignments, and the challenges in integrating MSAs with multiple orthogonal data such as cancer variants and post-translational modifications, which are often stored in heterogeneous data sources and formats. Here, we present the Multiple Sequence Alignment Ontology (MSAOnt), which represents a profile or consensus alignment in an ontological format. Subsets of the alignment are easily selected through the SPARQL Protocol and RDF Query Language for downstream statistical analysis or visualization. We have also created the Kinome Viewer (KinView), an interactive integrative visualization that places eukaryotic protein kinase cancer variants in the context of natural sequence variation and experimentally determined post-translational modifications, which play central roles in the regulation of cellular signaling pathways. Using KinView, we identified differential phosphorylation patterns between tyrosine and serine/threonine kinases in the activation segment, a major kinase regulatory region that is often mutated in proliferative diseases. We discuss cancer variants that disrupt phosphorylation sites in the activation segment, and show how KinView can be used as a comparative tool to identify differences and similarities in natural variation, cancer variants and post-translational modifications between kinase groups, families and subfamilies. Based on KinView comparisons, we identify and experimentally characterize a regulatory tyrosine (Y177PLK4) in the PLK4 C-terminal activation segment region termed the P+1 loop. To further demonstrate the application of KinView in hypothesis generation and testing, we formulate and validate a hypothesis explaining a novel predicted loss-of-function variant (D523NPKCβ) in the regulatory spine of PKCβ, a recently identified tumor suppressor kinase. KinView provides a novel, extensible interface for performing comparative analyses between subsets of kinases and for integrating multiple types of residue specific annotations in user friendly formats.

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Section: Resultsmentioning

confidence: 99%

KinView: a visual comparative sequence analysis tool for integrated kinome research

et al. 2016

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“…The array results for the ERK1 activation sites (T202 and Y204) at the ring-stage of P. falciparum development are however difficult to interpret as these signals indicate increases as well as decreases. ERK1 T207 is a known autophosphorylation regulatory site and showed a fold change value of 1.25 in trophozoite-infected red cells-, supporting that regulation of ERK1 activity occurs during infection 42 . These data support that P. falciparum iRBCs modify the host cell Raf/Mek/ERK pathway during growth and that the activity of RBC B-Raf is required for parasite maturation beyond ring stages.…”

Section: Resultsmentioning

confidence: 72%

Signalome-wide assessment of erythrocyte response toPlasmodiumreveals novel targets for host-directed antimalarial intervention

Adderley

Freyend

Jackson

et al. 2020

Preprint

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“…Nevertheless, a Tyr at this position is highly conserved among many Ser/Thr kinase subfamilies, and the identification of inhibitory phosphorylation at this position in other Ser/Thr kinases again illustrates that this kind of regulatory cross-talk between kinase families maybe more widespread than previously appreciated. 18 An independent study looking at the flip-side of the coin -phosphatases-arrived to similar conclusions. St-Denis et al used a combination of phosphatase interaction screens and a follow-up phenotypic screen to explore the cellular functions of protein phosphatase.…”

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confidence: 73%

Tyr(less) kinase signaling during mitosis

Elowe

2017

Cell Cycle

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Tyrosine phosphorylation is rare, representing only about 0.5% of phosphorylations in the cell under basal conditions. While mitogenic tyrosine kinase signaling has been extensively explored, the role of phosphotyrosine signaling across the cell cycle and in particular during mitosis is poorly understood.Two recent, independent studies tackled this question from different angles to reveal exciting new insights into the role of this modification during cell division. Caron et al. 1 exploited mitotic phosphoproteomics data sets to determine the extent of mitotic tyrosine phosphorylation, and St-Denis et al. 2 identified protein tyrosine phosphatases from all subfamilies as regulators of mitotic progression or spindle formation. These studied collectively revealed that tyrosine phosphorylation may play a more prominent and active role in mitotic progression than previously appreciated. Protein phosphorylation is well recognized as a major mode of post-translational regulation. The human genome encodes over 23,000 proteins; more than two-thirds phosphorylated. 3 Phosphorylation is a crucial component of signal transduction, regulating pathways that control processes from cell division to cell death. At the molecular level, reversible phosphorylation can lead to changes in protein structure and stability, protein-protein interactions, enzyme activation, or subcellular localization. Phosphorylation is most dynamic during the mitotic stage of the cell cycle, 4 and many mitotic phosphoproteome studies have resulted in a wealth of data on serine (Ser) and threonine (Thr) phosphorylation events. However, phosphotyrosine (pTyr) sites are relatively rare, and are underrepresented even in large scale mitosis-specific phosphoproteome studies. Seminal work from many groups in the 1980s, 1990s and early 2000s has revealed remarkable insight into how tyrosine (Tyr) phosphorylation regulates many aspects of growth and development. It is an integral component of cell surface signaling by receptors such as receptor tyrosine kinases, and integrins which signal in part via intracellular kinases such as the Src-family kinases (SFKs). 5 These cell surface signals are then propagated throughout the cytoplasm and nucleus through signaling networks often involving feedbacks and crosstalks to finally elicit the appropriate response. A number of tissue-specific pTyr screens have been reported (e.g. 6-8 ) but little is known about Tyr phosphorylation dynamics throughout the cell cycle, leaving a significant gap in our understanding of cell cycle control.The best understood pTyr site regulated during mitosis is arguably the inhibitory phosphorylation of cyclin-dependent kinase (CDK1) at Tyr, 15 which is catalyzed by WEE1 and MYT1, and whose dephosphorylation serves as the basis for the switch-like activity of CDK1/cyclin B at mitotic entry. 9 Tyr phosphorylation at the spindle was clearly demonstrated almost 20 years ago when pTyr-containing epitopes, detected by the monoclonal 4G10 pTyr antibody, were observed at kinetochores and cen...

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Regulatory roles of conserved phosphorylation sites in the activation T-loop of the MAP kinase ERK1

Cited by 31 publications

References 79 publications

KinView: a visual comparative sequence analysis tool for integrated kinome research

KinView: a visual comparative sequence analysis tool for integrated kinome research

Signalome-wide assessment of erythrocyte response toPlasmodiumreveals novel targets for host-directed antimalarial intervention

Tyr(less) kinase signaling during mitosis

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