Question

Immunology

Describe 2 ways that ubiquitinylation regulates signaling either positively or negatively.

What is the role of guanine nucleotide exchange factors in initiating signaling and what kind of signaling pathway do they initiate?

What is the target of LCK on the CD3 molecule and how does that influence the initiation of signaling when the TCR binds antigen?

Distinguish the roles of SH3 ligands and CD45 in the regulation of SRC family kinases

Explain how PLCgamma is activated and what the outcome of that activation produces.

What three transcription factors enter the nucleus when sufficient TCR signaling occurs and how does that lead to clonal expansion of antigen specific T cells?

Answer 1

Ubiquitin is a small protein that can be covalently linked to lysine residues of proteins targeted for intracellular degradation by proteasomes.

The Mechanism of Ubiquitination

The 76 amino acid protein ubiquitin is first activated by a ubiquitin activating enzyme (E1) in an ATP dependent process. An E2 ubiquitin conjugating enzyme then transfers activated ubiquitin via a thioester bond to a cysteine residue in its active site.

The ubiquitin-proteasome system exists in both the cytoplasm and the nucleus and is responsible for the degradation of many short-lived cellular proteins. Ubiquitination of the target protein can occur on an ε-amino group of an internal lysine or on the N terminus of the protein tagged for destruction.

Lck is a tyrosine kinase that is recruited to the cytoplasmic tails of the CD4 and CD8 coreceptors and is thus recruited to the TCR complex upon coreceptor binding to MHC. Active Lck directly phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3 chains of the TCR complex.

Ubiquitin is a small protein that is found in almost all cellular tissues in humans and other eukaryotic organisms, which helps to regulate the processes of other proteins in the body

Ubiquitination, the covalent attachment of ubiquitin to target proteins, has emerged as a ubiquitous post-translational modification (PTM) whose function extends far beyond its original role as a tag for protein degradation identified three decades ago. Although sharing parallel properties with phosphorylation, ubiquitination distinguishes itself in important ways. Nevertheless, the interplay and crosstalk between ubiquitination and phosphorylation events have become a recurrent theme in cell signalling regulation. Understanding how these two major PTMs intersect to regulate signal transduction is an important research question. In this review, we first discuss the involvement of ubiquitination in the regulation of the EGF-mediated ERK signalling pathway via the EGF receptor, highlighting the interplay between ubiquitination and phosphorylation in this cancer-implicated system and addressing open questions. The roles of ubiquitination in pathways crosstalking to EGFR/MAPK signalling will then be discussed. In the final part of the review, we demonstrate the rich and versatile dynamics of crosstalk between ubiquitination and phosphorylation by using quantitative modelling and analysis of network motifs commonly observed in cellular processes. We argue that given the overwhelming complexity arising from inter-connected PTMs, a quantitative framework based on systems biology and mathematical modelling is needed to efficiently understand their roles in cell signalling.

Guanine nucleotide exchange factors (GEFs) are proteins or protein domains involved in the activation of small GTPases. Small GTPases act as molecular switches in intracellular signaling pathways and have many downstream targets. ... GEFs function to promote the dissociation of GDP.

Helper T cells become activated when they are presented with peptide antigens by MHC class II molecules, which are expressed on the surface of antigen-presenting cells (APCs). Once activated, they divide rapidly and secrete cytokines that regulate or assist the immune response

Primary T-cell immunodeficiencies

T-cell signaling is often initiated by TCR binding to peptide-MHC complexes expressed on the surface of antigen presenting cells. This engagement leads to a series of intracellular signaling cascades that culminate in the generation of a T-cell response

The Src family tyrosine kinases (SFKs) play pivotal roles as molecular switches that link a variety of extracellular cues to intracellular signaling pathway. The function of SFK is regulated by phosphorylation at the C-terminal regulatory site mediated by Csk

PLC-β enzymatically cleaves the membrane phospholipid phosphoatidylinositol-4,5-bisphopshate (PIP2) into diacylglycerol (DAG) and inositol trisphosphate (IP3). Both DAG and IP3 act as important second messengers. DAG remains in the membrane where it recruits and activates protein kinase C.

Instead of adenylyl cyclase another enzyme called phospholipase C is activated by the dissasociated α subunit of the G protein. ... once activated phospholipase C catylizes (breaks down) phospholipids within the cell membrane into two specific molecules: DAG and iP3.

.Most transcription factors are located in the cytoplasm. After receiving a signal from the cell membrane signal transduction, transcription factors are activated and then translocated from the cytoplasm into the nucleus where they interact with the corresponding DNA frame (cis-acting elements)

The explosive increase in the number of lymphocytes, both B cells and T cells, from just a few to millions in the presence of an infection was discovered in the 1950s. The process, called clonal expansion, is what gives the adaptive immune system its extraordinary might and specificity.