SEL-5, A Serine/Threonine Kinase That Facilitates lin-12 Activity in Caenorhabditis elegans

Abstract Ligands present on neighboring cells activate receptors of the LIN-12/Notch family by inducing a proteolytic cleavage event that releases the intracellular domain. Mutations that appear to eliminate sel-5 activity are able to suppress constitutive activity of lin-12(d) mutations that are point mutations in the extracellular domain of LIN-12, but cannot suppress lin-12(intra), the untethered intracellular domain. These results suggest that sel-5 acts prior to or during ligand-dependent release of the intracellular domain. In addition, sel-5 suppression of lin-12(d) mutations is tissue specific: loss of sel-5 activity can suppress defects in the anchor cell/ventral uterine precursor cell fate decision and a sex myoblast/coelomocyte decision, but cannot suppress defects in two different ventral hypodermal cell fate decisions in hermaphrodites and males. sel-5 encodes at least two proteins, from alternatively spliced mRNAs, that share an amino-terminal region and differ in the carboxy-terminal region. The amino-terminal region contains the hallmarks of a serine/threonine kinase domain, which is most similar to mammalian GAK1 and yeast Pak1p.

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Tribbles homolog 2 (Trib2), a pseudo serine/threonine kinase in tumorigenesis and stem cell fate decisions

Cell Communication and Signaling ◽

10.1186/s12964-021-00725-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Yu Fang ◽

Angelina Olegovna Zekiy ◽

Farhoodeh Ghaedrahmati ◽

Anton Timoshin ◽

Maryam Farzaneh ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Fate ◽

Embryonic Stem ◽

Specific Cell ◽

Serine Threonine Kinase ◽

Stem Cell Fate ◽

Cell Fate Decisions ◽

Threonine Kinase ◽

Wide Range

AbstractThe family of Tribbles proteins play many critical nonenzymatic roles and regulate a wide range of key signaling pathways. Tribbles homolog 2 (Trib2) is a pseudo serine/threonine kinase that functions as a scaffold or adaptor in various physiological and pathological processes. Trib2 can interact with E3 ubiquitin ligases and control protein stability of downstream effectors. This protein is induced by mitogens and enhances the propagation of several cancer cells, including myeloid leukemia, liver, lung, skin, bone, brain, and pancreatic. Thus, Trib2 can be a predictive and valuable biomarker for the diagnosis and treatment of cancer. Recent studies have illustrated that Trib2 plays a major role in cell fate determination of stem cells. Stem cells have the capacity to self-renew and differentiate into specific cell types. Stem cells are important sources for cell-based regenerative medicine and drug screening. Trib2 has been found to increase the self-renewal ability of embryonic stem cells, the reprogramming efficiency of somatic cells, and chondrogenesis. In this review, we will focus on the recent advances of Trib2 function in tumorigenesis and stem cell fate decisions.

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Cell fate clusters in ICM organoids arise from cell fate heredity and division: a modelling approach

Scientific Reports ◽

10.1038/s41598-020-80141-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Tim Liebisch ◽

Armin Drusko ◽

Biena Mathew ◽

Ernst H. K. Stelzer ◽

Sabine C. Fischer ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Division ◽

Cell Fate ◽

Inner Cell Mass ◽

Cell Mass ◽

Cell Lineage ◽

Cell Fate Decision ◽

Cell Fate Decisions ◽

Chemical Signalling ◽

Fate Decision

AbstractDuring the mammalian preimplantation phase, cells undergo two subsequent cell fate decisions. During the first decision, the trophectoderm and the inner cell mass are formed. Subsequently, the inner cell mass segregates into the epiblast and the primitive endoderm. Inner cell mass organoids represent an experimental model system, mimicking the second cell fate decision. It has been shown that cells of the same fate tend to cluster stronger than expected for random cell fate decisions. Three major processes are hypothesised to contribute to the cell fate arrangements: (1) chemical signalling; (2) cell sorting; and (3) cell proliferation. In order to quantify the influence of cell proliferation on the observed cell lineage type clustering, we developed an agent-based model accounting for mechanical cell–cell interaction, i.e. adhesion and repulsion, cell division, stochastic cell fate decision and cell fate heredity. The model supports the hypothesis that initial cell fate acquisition is a stochastically driven process, taking place in the early development of inner cell mass organoids. Further, we show that the observed neighbourhood structures can emerge solely due to cell fate heredity during cell division.

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Evidence for Selection at thefusedLocus ofDrosophila virilis

Genetics ◽

10.1093/genetics/155.4.1701 ◽

2000 ◽

Vol 155 (4) ◽

pp. 1701-1709 ◽

Cited By ~ 3

Author(s):

Jorge Vieira ◽

Brian Charlesworth

Keyword(s):

Amino Acid ◽

Aspartic Acid ◽

Kinase Domain ◽

Drosophila Virilis ◽

Serine Threonine Kinase ◽

Threonine Kinase ◽

Usual Equilibrium ◽

Replacement Site ◽

Fused Gene ◽

Significant Linkage

AbstractThe genomic DNA sequence of a 2.4-kb region of the X-linked developmental gene fused was determined in 15 Drosophila virilis strains. One common replacement polymorphism is observed, where a negatively charged aspartic amino acid is replaced by the noncharged amino acid alanine. This replacement variant is located within the serine/threonine kinase domain of the fused gene and is present in ~50% of the sequences in our sample. Significant linkage disequilibrium is detected around this replacement site, although the fused gene is located in a region of the D. virilis X chromosome that seems to experience normal levels of recombination. In a 600-bp region around the replacement site, all eight alanine sequences are identical; of the six aspartic acid sequences, three are also identical. The occurrence of little or no variation within the aspartic acid and alanine haplotypes, coupled with the presence of several differences between them, is very unlikely under the usual equilibrium neutral model. Our results suggest that the fused alanine haplotypes have recently increased in frequency in the D. virilis population.

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Structural differences between repressed and derepressed forms of p60c-src

Molecular and Cellular Biology ◽

10.1128/mcb.9.6.2648-2656.1989 ◽

1989 ◽

Vol 9 (6) ◽

pp. 2648-2656

Author(s):

A MacAuley ◽

J A Cooper

Keyword(s):

Kinase Activity ◽

Kinase Domain ◽

Terminal Region ◽

Phosphorylation Sites ◽

Carboxy Terminus ◽

Kinase Activation ◽

Amino Terminal ◽

Structural Differences ◽

Carboxy Terminal ◽

Pronase E

The kinase activity of p60c-src is derepressed by removal of phosphate from Tyr-527, mutation of this residue to Phe, or binding of a carboxy-terminal antibody. We have compared the structures of repressed and active p60c-src, using proteases. All forms of p60c-src are susceptible to proteolysis at the boundary between the amino-terminal region and the kinase domain, but there are several sites elsewhere that are more sensitive to trypsin digestion in repressed than in derepressed forms of p60c-src. The carboxy-terminal tail (containing Tyr-527) is more sensitive to digestion by pronase E and thermolysin when Tyr-527 is not phosphorylated. The kinase domain fragment released with trypsin has kinase activity. Relative to intact p60c-src, the kinase domain fragment shows altered substrate specificity, diminished regulation by the phosphorylated carboxy terminus, and novel phosphorylation sites. The results identify parts of p60c-src that change conformation upon kinase activation and suggest functions for the amino-terminal region.

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Tyr198 is the Essential Autophosphorylation Site for STK16 Localization and Kinase Activity

International Journal of Molecular Sciences ◽

10.3390/ijms20194852 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4852 ◽

Cited By ~ 1

Author(s):

Junjun Wang ◽

Juanjuan Liu ◽

Xinmiao Ji ◽

Xin Zhang

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Kinase Activity ◽

Kinase Domain ◽

Serine Threonine Kinase ◽

Cycle Progression ◽

Threonine Kinase ◽

Cellular Processes ◽

Activation Segment ◽

And Function

STK16, reported as a Golgi localized serine/threonine kinase, has been shown to participate in multiple cellular processes, including the TGF-β signaling pathway, TGN protein secretion and sorting, as well as cell cycle and Golgi assembly regulation. However, the mechanisms of the regulation of its kinase activity remain underexplored. It was known that STK16 is autophosphorylated at Thr185, Ser197, and Tyr198 of the activation segment in its kinase domain. We found that STK16 localizes to the cell membrane and the Golgi throughout the cell cycle, but mutations in the auto-phosphorylation sites not only alter its subcellular localization but also affect its kinase activity. In particular, the Tyr198 mutation alone significantly reduced the kinase activity of STK16, abolished its Golgi and membrane localization, and affected the cell cycle progression. This study demonstrates that a single site autophosphorylation of STK16 could affect its localization and function, which provides insights into the molecular regulatory mechanism of STK16’s kinase activity.

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A Drosophila homolog of the Rac- and Cdc42-activated serine/threonine kinase PAK is a potential focal adhesion and focal complex protein that colocalizes with dynamic actin structures.

Molecular and Cellular Biology ◽

10.1128/mcb.16.5.1896 ◽

1996 ◽

Vol 16 (5) ◽

pp. 1896-1908 ◽

Cited By ~ 140

Author(s):

N Harden ◽

J Lee ◽

H Y Loh ◽

Y M Ong ◽

I Tan ◽

...

Keyword(s):

Focal Adhesion ◽

Cell Shape ◽

Focal Adhesions ◽

Leading Edge ◽

Epidermal Cells ◽

Dorsal Closure ◽

Serine Threonine Kinase ◽

Threonine Kinase ◽

Amino Terminal ◽

Drosophila Homolog

Changes in cell morphology are essential in the development of a multicellular organism. The regulation of the cytoskeleton by the Rho subfamily of small GTP-binding proteins is an important determinant of cell shape. The Rho subfamily has been shown to participate in a variety of morphogenetic processes during Drosophila melanogaster development. We describe here a Drosophila homolog, DPAK, of the serine/threonine kinase PAK, a protein which is a target of the Rho subfamily proteins Rac and Cdc42. Rac, Cdc42, and PAK have previously been implicated in signaling by c-Jun amino-terminal kinases. DPAK bound to activated (GTP-bound) Drosophila Rac (DRacA) and Drosophila Cdc42. Similarities in the distributions of DPAK, integrin, and phosphotyrosine suggested an association of DPAK with focal adhesions and Cdc42- and Rac-induced focal adhesion-like focal complexes. DPAK was elevated in the leading edge of epidermal cells, whose morphological changes drive dorsal closure of the embryo. We have previously shown that the accumulation of cytoskeletal elements initiating cell shape changes in these cells could be inhibited by expression of a dominant-negative DRacA transgene. We show that leading-edge epidermal cells flanking segment borders, which express particularly large amounts of DPAK, undergo transient losses of cytoskeletal structures during dorsal closure. We propose that DPAK may be regulating the cytoskeleton through its association with focal adhesions and focal complexes and may be participating with DRacA in a c-Jun amino-terminal kinase signaling pathway recently demonstrated to be required for dorsal closure.

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Identification of a Family of Vibrio Type III Secretion System Effectors That Contain a Conserved Serine/Threonine Kinase Domain

mSphere ◽

10.1128/msphere.00599-21 ◽

2021 ◽

Author(s):

N. Plaza ◽

I. M. Urrutia ◽

K. Garcia ◽

M. K. Waldor ◽

C. J. Blondel

Keyword(s):

Type Iii Secretion ◽

Type Iii Secretion System ◽

Kinase Domain ◽

Secretion System ◽

Effector Proteins ◽

Serine Threonine Kinase ◽

Content Type ◽

Threonine Kinase ◽

Type Iii ◽

Infected Cells

Vibrio parahaemolyticus is the leading bacterial cause of seafood-borne gastroenteritis worldwide. The pathogen relies on a type III secretion system to deliver a variety of effector proteins into the cytosol of infected cells to subvert cellular function.

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Epigenetic Control of Mesenchymal Stromal Cell Fate Decision

10.5772/intechopen.97086 ◽

2021 ◽

Author(s):

Haoli Ying ◽

Ruolang Pan ◽

Ye Chen

Keyword(s):

Cell Fate ◽

Molecular Mechanisms ◽

Epigenetic Modification ◽

Cell Types ◽

Connective Tissues ◽

Differentiation Potential ◽

Cell Fate Decisions ◽

Fate Decision ◽

Msc Differentiation

Mesenchymal stem cells (MSCs) are progenitors of connective tissues, which have emerged as important tools for tissue engineering owing to their differentiation potential in various cell types. The therapeutic utility of MSCs hinges upon our understanding of the molecular mechanisms involved in cellular fate decisions. Thus, the elucidation of the regulation of MSC differentiation has attracted increasing attention in recent years. A variety of external cues contribute to the process of MSC differentiation, including chemical, physical, and biological factors. Among the multiple factors that are known to affect cell fate decisions, the epigenetic regulation of MSC differentiation has become a research hotspot. In this chapter, we summarize recent progress in the determination of the effects of epigenetic modification on the multilineage differentiation of MSCs.

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Variability in β-catenin pulse dynamics in a stochastic cell fate decision in C. elegans

10.1101/245225 ◽

2018 ◽

Author(s):

Jason R. Kroll ◽

Jasonas Tsiaxiras ◽

Jeroen S. van Zon

Keyword(s):

Caenorhabditis Elegans ◽

Cell Fate ◽

Cell Fusion ◽

Precursor Cell ◽

Cell Fate Decision ◽

Absolute Level ◽

Cell Fate Decisions ◽

Pulse Dynamics ◽

Significant Variability ◽

Fate Decision

AbstractDuring development, cell fate decisions are often highly stochastic, but with the frequency of the different possible fates tightly controlled. To understand how signaling networks control the cell fate frequency of such random decisions, we studied the stochastic decision of the Caenorhabditis elegans P3.p cell to either fuse to the hypodermis or assume vulva precursor cell fate. Using time-lapse microscopy to measure the single-cell dynamics of two key inhibitors of cell fusion, the Hox gene LIN-39 and Wnt signaling through the β-catenin BAR-1, we uncovered significant variability in the dynamics of LIN-39 and BAR-1 levels. Most strikingly, we observed that BAR-1 accumulated in a single, 1-4 hour pulse at the time of the P3.p cell fate decision, with strong variability both in pulse slope and time of pulse onset. We found that the time of BAR-1 pulse onset was delayed relative to the time of cell fusion in mutants with low cell fusion frequency, linking BAR-1 pulse timing to cell fate outcome. Overall, a model emerged where animal-to-animal variability in LIN-39 levels and BAR-1 pulse dynamics biases cell fate by modulating their absolute level at the time cell fusion is induced. Our results highlight that timing of cell signaling dynamics, rather than its average level or amplitude, could play an instructive role in determining cell fate.Article summaryWe studied the stochastic decision of the Caenorhabditis elegans P3.p cell to either fuse to the hypodermis or assume vulva precursor cell fate. We uncovered significant variability in the dynamics of LIN-39/Hox and BAR-1/β-catenin levels, two key inhibitors of cell fusion. Surprisingly, we observed that BAR-1 accumulated in a 1-4 hour pulse at the time of the P3.p cell fate decision, with variable pulse slope and time of pulse onset. Our work suggests a model where animal-to-animal variability in LIN-39 levels and BAR-1 pulse dynamics biases cell fate by modulating their absolute level at the time cell fusion is induced.

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The C. elegans par-4 gene encodes a putative serine-threonine kinase required for establishing embryonic asymmetry

Development ◽

10.1242/dev.127.7.1467 ◽

2000 ◽

Vol 127 (7) ◽

pp. 1467-1475 ◽

Cited By ~ 6

Author(s):

J.L. Watts ◽

D.G. Morton ◽

J. Bestman ◽

K.J. Kemphues

Keyword(s):

Cell Cycle ◽

Kinase Domain ◽

Missense Mutations ◽

Serine Threonine Kinase ◽

Cell Stage ◽

Threonine Kinase ◽

C Elegans ◽

Human Kinase ◽

Early Embryos ◽

Peutz Jeghers Syndrome

During the first cell cycle of Caenorhabditis elegans embryogenesis, asymmetries are established that are essential for determining the subsequent developmental fates of the daughter cells. The maternally expressed par genes are required for establishing this polarity. The products of several of the par genes have been found to be themselves asymmetrically distributed in the first cell cycle. We have identified the par-4 gene of C. elegans, and find that it encodes a putative serine-threonine kinase with similarity to a human kinase associated with Peutz-Jeghers Syndrome, LKB1 (STK11), and a Xenopus egg and embryo kinase, XEEK1. Several strong par-4 mutant alleles are missense mutations that alter conserved residues within the kinase domain, suggesting that kinase activity is essential for PAR-4 function. We find that the PAR-4 protein is present in the gonads, oocytes and early embryos of C. elegans, and is both cytoplasmically and cortically distributed. The cortical distribution begins at the late 1-cell stage, is more pronounced at the 2- and 4-cell stages and is reduced at late stages of embryonic development. We find no asymmetry in the distribution of PAR-4 protein in C. elegans embryos. The distribution of PAR-4 protein in early embryos is unaffected by mutations in the other par genes.

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