Evolution of protein kinase substrate recognition at the active site

Bradley, David; Beltrão, Pedro

doi:10.1371/journal.pbio.3000341

Cited by 65 publications

(45 citation statements)

References 126 publications

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“…As observed for AKT (13) and many other kinases (45)(46)(47), the molecular basis for kinase substrate selectivity can depend critically on the residues neighboring the phosphorylation site. Yet it is important to understand that not all substrates identified for AKT isozymes include the same exact consensus motif EDITORS' PICK: Phosphorylation status regulates AKT1 selectivity (10).…”

Section: Phosphorylation Dependent Changes In the Akt1 Substrate Motifmentioning

confidence: 98%

Phosphorylation-dependent substrate selectivity of protein kinase B (AKT1)

Balasuriya

Davey

Johnson

et al. 2020

Journal of Biological Chemistry

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Protein kinase B (AKT1) is a central node in a signaling pathway that regulates cell survival. The diverse pathways regulated by AKT1 are communicated in the cell via the phosphorylation of perhaps more than 100 cellular substrates. AKT1 is itself activated by phosphorylation at Thr-308 and Ser-473. Despite the fact that these phosphorylation sites are biomarkers for cancers and tumor biology, their individual roles in shaping AKT1 substrate selectivity are unknown. We recently developed a method to produce AKT1 with programmed phosphorylation at either or both of its key regulatory sites. Here, we used both defined and randomized peptide libraries to map the substrate selectivity of site-specific, singly and doubly phosphorylated AKT1 variants. To globally quantitate AKT1 substrate preferences, we synthesized three AKT1 substrate peptide libraries: one based on 84 “known” substrates and two independent and larger oriented peptide array libraries (OPALs) of ∼1011 peptides each. We found that each phospho-form of AKT1 has common and distinct substrate requirements. Compared with pAKT1T308, the addition of Ser-473 phosphorylation increased AKT1 activities on some, but not all of its substrates. This is the first report that Ser-473 phosphorylation can positively or negatively regulate kinase activity in a substrate-dependent fashion. Bioinformatics analysis indicated that the OPAL-activity data effectively discriminate known AKT1 substrates from closely related kinase substrates. Our results also enabled predictions of novel AKT1 substrates that suggest new and expanded roles for AKT1 signaling in regulating cellular processes.

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Section: Phosphorylation Dependent Changes In the Akt1 Substrate Motifmentioning

confidence: 98%

Phosphorylation-dependent substrate selectivity of protein kinase B (AKT1)

Balasuriya

Davey

Johnson

et al. 2020

Journal of Biological Chemistry

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“…pSer/pThr-binding protein domains, such as WW, forkhead-associated (FHA), and 14-3-3, have also been identified to add complexity to phosphosignaling by recruiting partner proteins and serving as signaling hubs in a phosphorylation-dependent manner. For 14-3-3 proteins, the Mode 1 (RSX(pS/T)XP) and Mode 2 (RX(F/Y)X (pS)XP) consensus motifs of 14-3-3 binding sites [14,15], mostly in disordered protein regions, have been identified [16][17][18]. Therefore, these proteins can be considered an additional layer for amplification of complex pSer/ pThr signaling and the interplay with regulating kinases is well-established [15,17,19,20].…”

Section: Enzymes and Interactors Of The Pser/pthr Phosphoproteomementioning

confidence: 99%

Evolutionary crossroads of cell signaling: PP1 and PP2A substrate sites in intrinsically disordered regions

Hoermann

Köhn

2021

Biochemical Society Transactions

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Phosphorylation of the hydroxyl group of the amino acids serine and threonine is among the most prevalent post-translational modifications in mammalian cells. Phospho-serine (pSer) and -threonine (pThr) represent a central cornerstone in the cell's toolbox for adaptation to signal input. The true power for the fast modulation of the regulatory pSer/pThr sites arises from the timely attachment, binding and removal of the phosphate. The phosphorylation of serine and threonine by kinases and the binding of pSer/pThr by phosphorylation-dependent scaffold proteins is largely determined by the sequence motif surrounding the phosphorylation site (p-site). The removal of the phosphate is regulated by pSer/pThr-specific phosphatases with the two most prominent ones being PP1 and PP2A. For this family, recent advances brought forward a more complex mechanism for p-site selection. The interaction of regulatory proteins with the substrate protein constitutes a first layer for substrate recognition, but also interactions of the catalytic subunit with the amino acids in close proximity to pSer/pThr contribute to p-site selection. Here, we review the current pieces of evidence for this multi-layered, complex mechanism and hypothesize that, depending on the degree of higher structure surrounding the substrate site, recognition is more strongly influenced by regulatory subunits away from the active site for structured substrate regions, whereas the motif context is of strong relevance with p-sites in disordered regions. The latter makes these amino acid sequences crossroads for signaling and motif strength between kinases, pSer/pThr-binding proteins and phosphatases.

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“…Protein kinases have evolved to generate different kinase families, distinct in sequence, structure, and specificity [ 3 , 4 ]; the Tyrosine Kinase (TK) family stands out among them as a major research focus. In fact, members of the TK family, which exhibit a significant association with diseases, have been successfully targeted by chemical inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Lemur Tyrosine Kinases and Prostate Cancer: A Literature Review

Ferrari

Naponelli

Bettuzzi

2021

IJMS

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The members of the Lemur Tyrosine Kinases (LMTK1-3) subfamily constitute a group of three membrane-anchored kinases. They are known to influence a wide variety of key cellular events, often affecting cell proliferation and apoptosis. They have been discovered to be involved in cancer, in that they impact various signalling pathways that influence cell proliferation, migration, and invasiveness. Notably, in the context of genome-wide association studies, one member of the LMTK family has been identified as a candidate gene which could contribute to the development of prostate cancer. In this review, of published literature, we present evidence on the role of LMTKs in human prostate cancer and model systems, focusing on the complex network of interacting partners involved in signalling cascades that are frequently activated in prostate cancer malignancy. We speculate that the modulators of LMTK enzyme expression and activity would be of high clinical relevance for the design of innovative prostate cancer treatment.

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Evolution of protein kinase substrate recognition at the active site

Cited by 65 publications

References 126 publications

Phosphorylation-dependent substrate selectivity of protein kinase B (AKT1)

Phosphorylation-dependent substrate selectivity of protein kinase B (AKT1)

Evolutionary crossroads of cell signaling: PP1 and PP2A substrate sites in intrinsically disordered regions

Lemur Tyrosine Kinases and Prostate Cancer: A Literature Review

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