The role of USP7 in the Shoc2-ERK1/2 signaling axis and Noonan-like syndrome with loose anagen hair.

The ERK1/2 (also known as MAPK3 and MAPK1, respectively) signaling pathway is critical in organismal development and tissue morphogenesis. Deregulation of this pathway leads to congenital abnormalities with severe developmental dysmorphisms. The core ERK1/2 cascade relies on scaffold proteins, such as Shoc2 to guide and fine-tune its signals.

The leucine-rich repeat signaling scaffolds Shoc2 and Erbin: cellular mechanism and role in disease.

Leucine-rich repeat-containing proteins (LRR proteins) are involved in supporting a large number of cellular functions. In this review, we summarize recent advancements in understanding functions of the LRR proteins as signaling scaffolds. In particular, we explore what we have learned about the mechanisms of action of the LRR scaffolds Shoc2 and Erbin and their roles in normal development and disease.

Single-domain antibodies for functional targeting of the signaling scaffold Shoc2.

The accurate transmission of signals by the canonical ERK1/2 kinase pathway critically relies on the proper assembly of an intricate multiprotein complex by the scaffold protein Shoc2. However, the details of the mechanism by which Shoc2 guides ERK1/2 signals are not clear, in part, due to the lack of research tools targeting specific protein binding moieties of Shoc2. We report generation and characterization of single domain antibodies against human Shoc2 using a universal synthetic library of humanized nanobodies.

VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: novel insights into IBMPFD pathology.

Valosin-containing protein (VCP), also named p97, is an essential hexameric AAA+ ATPase with diverse functions in the ubiquitin system. Here we demonstrate that VCP is critical in controlling signals transmitted via the essential Shoc2-ERK1/2 signaling axis. The ATPase activity of VCP modulates the stoichiometry of HUWE1 in the Shoc2 complex as well as HUWE1-mediated allosteric ubiquitination of the Shoc2 scaffold and the RAF-1 kinase.

Hematopoietic and neural crest defects in zebrafish shoc2 mutants: a novel vertebrate model for Noonan-like syndrome.

The extracellular signal-related kinase 1 and 2 (ERK1/2) pathway is a highly conserved signaling cascade with numerous essential functions in development. The scaffold protein Shoc2 amplifies the activity of the ERK1/2 pathway and is an essential modulator of a variety of signaling inputs. Germline mutations in Shoc2 are associated with the human developmental disease known as the Noonan-like syndrome with loose anagen hair.

[The Russian consensus on the diagnosis and treatment of chronic pancreatitis: Enzyme replacement therapy].

Pancreatology Club Professional Medical Community, 1A.S. Loginov Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow; 2A.

Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes.

Insulin-degrading enzyme (IDE) hydrolyzes bioactive peptides, including insulin, amylin, and the amyloid β peptides. Polyanions activate IDE toward some substrates, yet an endogenous polyanion activator has not yet been identified. Here we report that inositol phosphates (InsPs) and phosphatdidylinositol phosphates (PtdInsPs) serve as activators of IDE.

The function of Shoc2: A scaffold and beyond.

The extracellular signal-regulated kinase (ERK1/2) cascade regulates a myriad of functions in multicellular organisms. Scaffold proteins provide critical spatial and temporal control over the specificity of signaling. Shoc2 is a scaffold that accelerates activity of the ERK1/2 pathway.

Data set for transcriptional response to depletion of the Shoc2 scaffolding protein.

The Suppressor of Clear, Caenorhabditis elegans Homolog (SHOC2) is a scaffold protein that positively modulates activity of the RAS/ERK1/2 MAP kinase signaling cascade. We set out to understand the ERK1/2 pathway transcriptional response transduced through the SHOC2 scaffolding module. This data article describes raw gene expression within triplicates of kidney fibroblast-like Cos1 cell line expressing non-targeting shRNA (Cos-NT) and triplicates of Cos1 cells depleted of SHOC2 using shRNA (Cos-LV1) upon activation of ERK1/2 pathway by the Epidermal Growth Factor Receptor (EGFR).

Shoc2-tranduced ERK1/2 motility signals--Novel insights from functional genomics.

The extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway plays a central role in defining various cellular fates. Scaffold proteins modulating ERK1/2 activity control growth factor signals transduced by the pathway. Here, we analyzed signals transduced by Shoc2, a critical positive modulator of ERK1/2 activity.

Spatial control of Shoc2-scaffold-mediated ERK1/2 signaling requires remodeling activity of the ATPase PSMC5.

The scaffold protein Shoc2 accelerates activity of the ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1) pathway. Mutations in Shoc2 result in Noonan-like RASopathy, a developmental disorder with a wide spectrum of symptoms. The amplitude of the ERK1/2 signals transduced through the complex is fine-tuned by the HUWE1-mediated ubiquitylation of Shoc2 and its signaling partner RAF-1.

A Novel SHOC2 Variant in Rasopathy.

Rasopathies are a group of genetic disorders caused by germline mutations in multiple genes of the Extracellular signal-Regulated Kinases 1 and 2 (ERK1/2) pathway. The only previously identified missense mutation in SHOC2, a scaffold protein of the ERK1/2 pathway, led to Noonan-like syndrome with loose anagen hair. Here, we report a novel mutation in SHOC2(c.

HUWE1 is a molecular link controlling RAF-1 activity supported by the Shoc2 scaffold.

Scaffold proteins play a critical role in controlling the activity of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Shoc2 is a leucine-rich repeat scaffold protein that acts as a positive modulator of ERK1/2 signaling. However, the precise mechanism by which Shoc2 modulates the activity of the ERK1/2 pathway is unclear.

[The classification of obstructive jaundice severity].

It was analyzed the results of examination and surgical treatment of 338 patients with obstructive jaundice. The patients were operated in 2004-2012 years. 148 patients had benign jaundice and 190 patients had malignancy genesis of jaundice.

Dynamic changes in dopamine neuron function after DNSP-11 treatment: effects in vivo and increased ERK 1/2 phosphorylation in vitro.

Glial cell-line derived neurotrophic factor (GDNF) has demonstrated robust effects on dopamine (DA) neuron function and survival. A post-translational processing model of the human GDNF proprotein theorizes the formation of smaller, amidated peptide(s) from the proregion that exhibit neurobiological function, including an 11-amino-acid peptide named dopamine neuron stimulating peptide-11 (DNSP-11). A single treatment of DNSP-11 was delivered to the substantia nigra in the rat to investigate effects on DA-neuron function.

Visualizing of signaling proteins on endosomes utilizing knockdown and reconstitution approach.

Spatial distribution of intracellular signaling molecules and assembly of signaling complexes are yet to be fully understood. Studies of signaling events in time or space present a particular challenge due to the adverse effects that overexpression of signaling proteins may have on their functions and localization. To follow the distribution of signaling proteins in living cells we developed a methodology named knockdown and reconstitution (KDAR) that allows one to visualize proteins at levels of expression that are close to physiological.

Functional Integration of the Conserved Domains of Shoc2 Scaffold.

Shoc2 is a positive regulator of signaling to extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Shoc2 is also proposed to interact with RAS and Raf-1 in order to accelerate ERK1/2 activity. To understand the mechanisms by which Shoc2 regulates ERK1/2 activation by the epidermal growth factor receptor (EGFR), we dissected the role of Shoc2 structural domains in binding to its signaling partners and its role in regulating ERK1/2 activity.

Shoc2 is targeted to late endosomes and required for Erk1/2 activation in EGF-stimulated cells.

Shoc2 is the putative scaffold protein that interacts with RAS and RAF, and positively regulates signaling to extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). To elucidate the mechanism by which Shoc2 regulates ERK1/2 activation by the epidermal growth factor (EGF) receptor (EGFR), we studied subcellular localization of Shoc2. Upon EGFR activation, endogenous Shoc2 and red fluorescent protein tagged Shoc2 were translocated from the cytosol to a subset of late endosomes containing Rab7.

[Rate of biliary ducts' decompression by the tumorous obstructive jaundice].

Results of biliary decompression were analyzed in 185 patients with malignant obstructive jaundice. Among them 85 patients underwent nasobiliary drainage, 37 - percutaneous transhepatic bile drainage and 63 - cholecystectomy. Dynamics in biochemical indices of blood serum, cholangiomanometry and jaundice response to decompression according to T.

[Postoperative biliary complications after liver resections].

Postoperative biliary complications (BC) after liver resections carried out from 1990 to 2009 were analyzed in 216 patients. Among them - 139 women and 77 men aged 15-79 years (mean age 49,8±0,9 years). Complications in early postoperative period were observed in 110 patients (50,9%); among them BC - in 27 patients (12,2%), bilomas - in 6, external biliation - in 14, abscesses - in 7.