scholarly journals Mammalian Hippo signalling: a kinase network regulated by protein–protein interactions

2012 ◽  
Vol 40 (1) ◽  
pp. 124-128 ◽  
Author(s):  
Alexander Hergovich
Keyword(s):  
Protein Interactions ◽  
Tumour Suppressor ◽  
Protein Protein Interactions ◽  
Large Tumour ◽  
Serine Threonine Kinase ◽  
Ww Domains ◽  
Threonine Kinase ◽  
Signalling Molecules ◽  
Kinase Cascade ◽  
Hippo Signalling

The Hippo signal transduction cascade controls cell growth, proliferation and death, all of which are frequently deregulated in tumour cells. Since initial studies in Drosophila melanogaster were instrumental in defining Hippo signalling, the machinery was named after the central Ste20-like kinase Hippo. Moreover, given that loss of Hippo signalling components Hippo, Warts, and Mats resulted in uncontrolled tissue overgrowth, Hippo signalling was defined as a tumour-suppressor cascade. Significantly, all of the core factors of Hippo signalling have mammalian orthologues that functionally compensate for loss of their counterparts in Drosophila. Furthermore, studies in Drosophila and mammalian cell systems showed that Hippo signalling represents a kinase cascade that is tightly regulated by PPIs (protein–protein interactions). Several Hippo signalling molecules contain SARAH (Salvador/RASSF1A/Hippo) domains that mediate specific PPIs, thereby influencing the activities of MST1/2 (mammalian Ste20-like serine/threonine kinase 1/2) kinases, the human Hippo orthologues. Moreover, WW domains are present in several Hippo factors, and these domains also serve as interaction surfaces for regulatory PPIs in Hippo signalling. Finally, the kinase activities of LATS1/2 (large tumour-suppressor kinase 1/2), the human counterparts of Warts, are controlled by binding to hMOB1 (human Mps one binder protein 1), the human Mats. Therefore Hippo signalling is regulated by PPIs on several levels. In the present paper, I review the current understanding of how these regulatory PPIs are regulated and contribute to the functionality of Hippo signalling.

scholarly journals The PASTA domains of Bacillus subtilis PBP2B stabilize the interaction of PBP2B with DivIB

2019 ◽  
Author(s):  
Danae Morales Angeles ◽  
Alicia Macia-Valero ◽  
Laura C. Bohorquez ◽  
Dirk-Jan Scheffers
Keyword(s):  
Bacillus Subtilis ◽  
Cell Division ◽  
Protein Interactions ◽  
Bacterial Cell Division ◽  
Penicillin Binding Protein ◽  
Protein Protein Interactions ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Two Hybrid

AbstractBacterial cell division is mediated by a protein complex known as the divisome. Many protein-protein interactions in the divisome have been characterized. In this report, we analyse the role of the PASTA (Penicillin binding protein And Serine Threonine kinase Associated)-domains of Bacillus subtilis PBP2B. PBP2B itself is essential and cannot be deleted, but removing the PBP2B PASTA domains results in impaired cell division and a heat sensitive phenotype. This resembles the deletion of divIB, a known interaction partner of PBP2B. Bacterial two hybrid and co-immunoprecipitation analyses show that the interaction between PBP2B and DivIB is weakened when the PBP2B PASTA domains are removed. Combined, our results show that the PBP2B PASTA domains are required to stabilize the interaction between PBP2B and DivIB.

scholarly journals The PASTA domains of Bacillus subtilis PBP2B strengthen the interaction of PBP2B with DivIB

Microbiology ◽  
2020 ◽  
Vol 166 (9) ◽  
pp. 826-836 ◽  
Author(s):  
Danae Morales Angeles ◽  
Alicia Macia-Valero ◽  
Laura C. Bohorquez ◽  
Dirk-Jan Scheffers
Keyword(s):  
Bacillus Subtilis ◽  
Cell Division ◽  
Protein Interactions ◽  
Bacterial Cell Division ◽  
Penicillin Binding Protein ◽  
Protein Protein Interactions ◽  
Serine Threonine Kinase ◽  
Content Type ◽  
Threonine Kinase

Bacterial cell division is mediated by a protein complex known as the divisome. Many protein–protein interactions in the divisome have been characterized. In this report, we analyse the role of the PASTA (Penicillin-binding protein And Serine Threonine kinase Associated) domains of Bacillus subtilis PBP2B. PBP2B itself is essential and cannot be deleted, but removing the PBP2B PASTA domains results in impaired cell division and a heat-sensitive phenotype. This resembles the deletion of divIB, a known interaction partner of PBP2B. Bacterial two-hybrid and co-immunoprecipitation analyses show that the interaction between PBP2B and DivIB is weakened when the PBP2B PASTA domains are removed. Combined, our results show that the PBP2B PASTA domains are required to strengthen the interaction between PBP2B and DivIB.

scholarly journals Regulation of the tumour suppressor Fbw7α by PKC-dependent phosphorylation and cancer-associated mutations

2010 ◽  
Vol 432 (1) ◽  
pp. 77-87 ◽  
Author(s):  
Joanne Durgan ◽  
Peter J. Parker
Keyword(s):  
Mammalian Cells ◽  
Tumour Suppressor ◽  
Dependent Manner ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Pkc Protein Kinase C ◽  
Specific Regulation ◽  
The Relationship ◽  
Substrate Binding Domain

Fbw7 (F-box WD40 protein 7) is a major tumour suppressor, which mediates the degradation of several potent oncogenes. PKC (protein kinase C) comprises a serine/threonine kinase family that can promote transformation when dysregulated. In the present study, we investigated the relationship between Fbw7 and PKC. Multiple members of the PKC superfamily interact with the substrate-binding domain of Fbw7. However, we find no evidence for Fbw7-mediated degradation of PKC. Instead, we demonstrate that Fbw7 is a novel substrate for PKC. Two residues within the isoform-specific N-terminus of Fbw7α are phosphorylated in a PKC-dependent manner, both in vitro and in mammalian cells (Ser10 and Ser18). Mutational analyses reveal that phosphorylation of Fbw7α at Ser10 can regulate its nuclear localization. Cancer-associated mutations in nearby residues (K11R and the addition of a proline residue at position 16) influence Fbw7α localization in a comparable manner, suggesting that mislocalization of this protein may be of pathological significance. Together these results provide evidence for both physical and functional interactions between the PKC and Fbw7 families, and yield insights into the isoform-specific regulation of Fbw7α.

scholarly journals Structure and function of steroid receptor AF1 transactivation domains: induction of active conformations

2005 ◽  
Vol 391 (3) ◽  
pp. 449-464 ◽  
Author(s):  
Derek N. Lavery ◽  
Iain J. Mcewan
Keyword(s):  
Protein Interactions ◽  
Functional Model ◽  
Binding Domain ◽  
Protein Protein Interactions ◽  
Receptor Proteins ◽  
Signalling Molecules ◽  
Transactivation Domains ◽  
Induced Folding ◽  
Α Helix ◽  
And Function

Steroid hormones are important endocrine signalling molecules controlling reproduction, development, metabolism, salt balance and specialized cellular responses, such as inflammation and immunity. They are lipophilic in character and act by binding to intracellular receptor proteins. These receptors function as ligand-activated transcription factors, switching on or off networks of genes in response to a specific hormone signal. The receptor proteins have a conserved domain organization, comprising a C-terminal LBD (ligand-binding domain), a hinge region, a central DBD (DNA-binding domain) and a highly variable NTD (N-terminal domain). The NTD is structurally flexible and contains surfaces for both activation and repression of gene transcription, and the strength of the transactivation response has been correlated with protein length. Recent evidence supports a structural and functional model for the NTD that involves induced folding, possibly involving α-helix structure, in response to protein–protein interactions and structure-stabilizing solutes.

scholarly journals A protein tertiary structure mimetic modulator of the Hippo signalling pathway

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hélène Adihou ◽  
Ranganath Gopalakrishnan ◽  
Tim Förster ◽  
Stéphanie M. Guéret ◽  
Raphael Gasper ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Interactions ◽  
Tertiary Structure ◽  
Hippo Pathway ◽  
Signalling Pathway ◽  
Protein Protein Interactions ◽  
Protein Tertiary Structure ◽  
A Cell ◽  
Chemical Modulation ◽  
Hippo Signalling

Abstract Transcription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein–protein interactions (PPI). The chemical modulation of transcription factor activity is a long-standing goal in drug discovery but hampered by the difficulties associated with the targeting of PPIs, in particular when extended and flat protein interfaces are involved. Peptidomimetics have been applied to inhibit PPIs, however with variable success, as for certain interfaces the mimicry of a single secondary structure element is insufficient to obtain high binding affinities. Here, we describe the design and characterization of a stabilized protein tertiary structure that acts as an inhibitor of the interaction between the transcription factor TEAD and its co-repressor VGL4, both playing a central role in the Hippo signalling pathway. Modification of the inhibitor with a cell-penetrating entity yielded a cell-permeable proteomimetic that activates cell proliferation via regulation of the Hippo pathway, highlighting the potential of protein tertiary structure mimetics as an emerging class of PPI modulators.

Protein-protein interactions in the yeast pheromone response pathway: Ste5p interacts with all members of the MAP kinase cascade.

Genetics ◽  
1994 ◽  
Vol 138 (3) ◽  
pp. 609-619 ◽  
Author(s):  
J A Printen ◽  
G F Sprague
Keyword(s):  
Map Kinase ◽  
Protein Interactions ◽  
Map Kinases ◽  
Central Element ◽  
Signal Propagation ◽  
Protein Protein Interactions ◽  
Pheromone Response ◽  
Pheromone Response Pathway ◽  
Map Kinase Cascade ◽  
Kinase Cascade

Abstract We have used the two-hybrid system of Fields and Song to identify protein-protein interactions that occur in the pheromone response pathway of the yeast Saccharomyces cerevisiae. Pathway components Ste4p, Ste5p, Ste7p, Ste11p, Ste12p, Ste20p, Fus3p and Kss1p were tested in all pairwise combinations. All of the interactions we detected involved at least one member of the MAP kinase cascade that is a central element of the response pathway. Ste5p, a protein of unknown biochemical function, interacted with protein kinases that operate at each step of the MAP kinase cascade, specifically with Ste11p (an MEKK), Ste7p (an MEK), and Fus3p (a MAP kinase). This finding suggests that one role of Ste5p is to serve as a scaffold to facilitate interactions among members of the kinase cascade. In this role as facilitator, Ste5p may make both signal propagation and signal attenuation more efficient. Ste5p may also help minimize cross-talk with other MAP kinase cascades and thus ensure the integrity of the pheromone response pathway. We also found that both Ste11p and Ste7p interact with Fus3p and Kss1p. Finally, we detected an interaction between one of the MAP kinases, Kss1p, and a presumptive target, the transcription factor Ste12p. We failed to detect interactions of Ste4p or Ste20p with any other component of the response pathway.

scholarly journals The conserved Pkh–Ypk kinase cascade is required for endocytosis in yeast

2002 ◽  
Vol 156 (2) ◽  
pp. 241-248 ◽  
Author(s):  
Amy K.A. deHart ◽  
Joshua D. Schnell ◽  
Damian A. Allen ◽  
Linda Hicke
Keyword(s):  
Fluid Phase ◽  
Receptor Internalization ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Extracellular Signals ◽  
Fluid Phase Endocytosis ◽  
Endocytic Machinery ◽  
Kinase Cascade ◽  
Signaling Receptors ◽  
Mutant Cells

Internalization of activated signaling receptors by endocytosis is one way cells downregulate extracellular signals. Like many signaling receptors, the yeast α-factor pheromone receptor is downregulated by hyperphosphorylation, ubiquitination, and subsequent internalization and degradation in the lysosome-like vacuole. In a screen to detect proteins involved in ubiquitin-dependent receptor internalization, we identified the sphingoid base–regulated serine–threonine kinase Ypk1. Ypk1 is a homologue of the mammalian serum– and glucocorticoid-induced kinase, SGK, which can substitute for Ypk1 function in yeast. The kinase activity of Ypk1 is required for receptor endocytosis because mutations in two residues important for its catalytic activity cause a severe defect in α-factor internalization. Ypk1 is required for both receptor-mediated and fluid-phase endocytosis, and is not necessary for receptor phosphorylation or ubiquitination. Ypk1 itself is phosphorylated by Pkh kinases, homologues of mammalian PDK1. The threonine in Ypk1 that is phosphorylated by Pkh1 is required for efficient endocytosis, and pkh mutant cells are defective in α-factor internalization and fluid-phase endocytosis. These observations demonstrate that Ypk1 acts downstream of the Pkh kinases to control endocytosis by phosphorylating components of the endocytic machinery.

scholarly journals Target recognition in tandem WW domains: complex structures for parallel and antiparallel ligand orientation in h-FBP21 tandem WW

2021 ◽  
Author(s):  
Marius T. Wenz ◽  
Miriam Bertazzon ◽  
Jana Sticht ◽  
Stevan Aleksić ◽  
Daniela Gjorgjevikj ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Tandem Repeats ◽  
Molecular Simulations ◽  
Peptide Sequence ◽  
Complex Structures ◽  
Protein Protein Interactions ◽  
Ww Domains ◽  
Binding Partner ◽  
Density Based Clustering ◽  
Ligand Orientation

Protein-protein interactions often rely on specialized recognition domains, such as WW domains, which bind to specific proline-rich sequences. The specificity of these protein-protein interactions can be increased by tandem repeats, i.e. two WW domains connected by a linker. With a flexible linker, the WW domains can move freely with respect to each other. Additionally, the tandem WW domains can bind in two different orientations to their target sequences. This makes the elucidation of complex structures of tandem WW domains extremely challenging. Here, we identify and characterize two complex structures of the tandem WW domain of human formin-binding protein 21 and a peptide sequence from its natural binding partner, the core-splicing protein SmB/B′. The two structures differ in the ligand orientation, and consequently also in the relative orientation of the two WW domains. We analyze and probe the interactions in the complexes by molecular simulations and NMR experiments. The workflow to identify the complex structures uses molecular simulations, density-based clustering and peptide docking. It is designed to systematically generate possible complex structures for repeats of recognition domains. These stuctures will help us to understand the synergistic and multivalency effects that generate the astonishing versatility and specificity of protein-protein interactions.

scholarly journals WW Domains of Rsp5p Define Different Functions: Determination of Roles in Fluid Phase and Uracil Permease Endocytosis in Saccharomyces cerevisiae

Genetics ◽  
2001 ◽  
Vol 157 (1) ◽  
pp. 91-101 ◽  
Author(s):  
Beata Gajewska ◽  
Joanna Kamińska ◽  
Alicja Jesionowska ◽  
Nancy C Martin ◽  
Anita K Hopper ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Fluid Phase ◽  
Temperature Sensitive ◽  
Protein Protein Interactions ◽  
Ww Domains ◽  
Ubiquitin Protein Ligase ◽  
Cellular Processes ◽  
Fluid Phase Endocytosis ◽  
Ubiquitination Pathway ◽  
Punctate Pattern

Abstract Rsp5p, ubiquitin-protein ligase, an enzyme of the ubiquitination pathway, contains three WW domains that mediate protein-protein interactions. To determine if these domains adapt Rsp5p to a subset of substrates involved in numerous cellular processes, we generated mutations in individual or combinations of the WW domains. The rsp5-w1, rsp5-w2, and rsp5-w3 mutant alleles complement RSP5 deletions at 30°. Thus, individual WW domains are not essential. Each rsp5-w mutation caused temperature-sensitive growth. Among variants with mutations in multiple WW domains, only rsp5-w1w2 complemented the deletion. Thus, the WW3 domain is sufficient for Rsp5p essential functions. To determine whether rsp5-w mutations affect endocytosis, fluid phase and uracil permease (Fur4p) endocytosis was examined. The WW3 domain is important for both processes. WW2 appears not to be important for fluid phase endocytosis whereas it is important for Fur4p endocytosis. In contrast, the WW1 domain affects fluid phase endocytosis, but it does not appear to function in Fur4p endocytosis. Thus, various WW domains play different roles in the endocytosis of these two substrates. Rsp5p is located in the cytoplasm in a punctate pattern that does not change during the cell cycle. Altering WW domains does not change the location of Rsp5p.

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