Cancer

Succinate dehydrogenase (SDH) is a highly conserved protein complex located on the inner mitochondrial membrane where it functions during the Krebs cycle by oxidizing succinate to fumarate (1). This reaction is also important for feeding electrons into the electron transport chain. SDH complex contains four subunits: SDH-A, -B, -C, and -D. Mutation of SDH-A often leads to mitochondrial encephalopathy while mutations to subunits B, C, and D lead to tumors of the head and neck (1).

Transforming growth factor-beta receptor III (TGF-beta RIII) is one of three receptors for the secreted growth factor TGF-beta. Unlike type I and type II TGF-beta receptors, TGF-beta RIII does not participate directly in the propagation of intracellular signaling in response to TGF-beta binding (1). TGF-beta RIII typically functions as a coreceptor for TGF-beta by binding the ligand with high affinity in order to regulate signaling. TGF-beta RIII contains a large glycosylated extracellular domain and a small intracellular domain.

Cathepsins are a family of lysosomal proteases (serine, aspartic and cysteine proteases) that acts in conjunction with lipases and nucleases to degrade biological macromolecules in the lysosomes (1). While most cathepsins are ubiquitously expressed to support normal lysosomal degradation, cathepsin B is unique for its role in various pathologies and malignancies (2). Cathepsin B is often overexpressed and alternatively spliced in cancer cells (2).

Ki-67/MKI67 is an antigen which is expressed during G1, S, G2, and M phases of the cell cycle (mitotically active cells), but not during G0 phase (resting cells). It is a large protein with expected molecular weight of about 395 kDa, and it has a very complex localization pattern within the nucleus, one which changes during cell cycle progression. During interphase, Ki-67 antigen can be exclusively detected in the nucleus, whereas in mitotic phase, most of Ki67 pool gets relocated to the chromosomal surface.

Protein kinase R (PKR) is an intracellular stress-sensing protein that is able to detect and respond to viral infections. While PKR is able to sense and respond to a variety of signals, dsRNA is a well-characterized ligand. dsRNA produced during viral replication binds to PKR and induces a conformational change, dimerization, and exposure of the catalytic autophosphorylation site (1). Once in this active form PKR is able to phosphorylate substrates to regulate cell growth and stress responses.

UV resistance-associated gene (UVRAG) is a tumor suppressor that is commonly mutated in colon and breast cancer. While UVRAG was discovered for its ability to complement UV sensitivity in xeroderma pigmentosum cells, its main functions are in autophagy, endocytosis, and apoptosis. During autophagy UVRAG interacts with Beclin 1 to promote autophagosome formation. UVRAG can also interact with VPS16 to recruit membrane fusion machinery to mediate autophagosome maturation.

S6K is a serine/threonine kinase that is a member of the ribosomal S6 kinase (RSK) family. S6K exists in two main isoforms, S6K1 and S6K2, which can also be alternatively spliced to produce different splice forms. S6K1 has two major splicing products that are approximately 70 kDa and 85 kDa, known as p70S6K and p85S6K respectively. S6K is activated via phosphorylation by mTORC1 which relieves the autoinhibition of S6K. Active S6K phosphorylates the ribosomal S6 protein, which induces protein synthesis and cell growth and proliferation.

CD98 is a heterodimeric glycoprotein that contains an 80 kDa heavy chain and a 40 kDa light chain. The CD98 heavy chain is also known as the 4F2 antigen heavy chain or FRP-1, and it is encoded by the SLC3A2 gene. The CD98 heavy chain is capable of binding to β-integrins to mediate cell adhesion, motility, growth, and survival (1). Meanwhile, the CD98 light chain allows amino acid transport. Different isoforms of the light chain allow expression of six different L-amino acid transporters.

Akt1 is one of three isoforms of Akt belonging to the AGC family of serine/threonine kinases (Akt1, Akt2, and Akt3). All Akt isoforms contain an N-terminal Plekstrin Homology (PH) domain, a C-terminal regulatory domain, and a central catalytic kinase domain (1). Akt is a major downstream target of the PI3-K signaling pathway. The Akt1 isoform is fully activated by phosphorylation at three sites- T308, T450, and S473. Akt1 resides in an inactive state due to intramolecular interactions between the PH domain and the kinase domain.

TSC2 is a tumor suppressor gene that encodes a 200 kDa protein called tuberin. TSC2 heterodimerizes with TSC1 to form a complex with GTPase-activating protein (GAP) activity. The C-terminus of TSC2 contains the GAP domain responsible for this catalytic activity. The complex was first discovered through its role in the tumor-forming condition Tuberous Sclerosis. Mutations in TSC1 and TSC2 can either destabilize the complex or compromise the GAP activity. The TSC1-TSC2 complex acts as a GAP for the small G-protein Rheb, expressed ubiquitously throughout the body (1).