Signal Transduction

By Christina Towers, PhD.

By Jamshed Arslan Pharm.D.

By Jamshed Arslan Pharm.D.

Signal transducer and activator of transcription 3 (STAT3) is an important oncogenic transcriptional factor that mediates tumor induced immune suppression.  Specifically, STAT3 transmits signals from cytokines and growth factor receptors in the plasma membrane (PM) to the nucleus, where they alter gene transcription.  Because of this transcriptional regulatory role, STAT3 also plays a part in regulating transcription of many critical genes that are involved in apoptosis, cell differentiation, immune response, tumor formation and more.  Using a

RelA (also known as p65) is an NF-kB family member and a subunit of the NF-kB transcription factor complex.  The mammalian NF-kB family has five members (NF-kB1, NF-kB2, RelA (p65), RelB, and c-Rel), each of which contains an N-terminal Rel homology domain. Active NF-kB protein complexes are dimeric (hetero- or homo-), and are made up of two family members. NF-kB signaling is activated in response to many different types of stimuli and modulates transcription of numerous downstream targets.

The structure and organization of the plasma membrane is maintained by an underlying network of cytoskeletal proteins including actin and spectrin. Adducin, a member of this protein network, binds to bundles and caps actin filaments and links them to spectrin. Adducin’s role in organizing the cytoskeletal meshwork at the plasma membrane is important in signal transduction, cell-cell adhesion, and cell migration (1).

The heat-shock protein 90 (HSP90) family is a group of highly conserved molecular chaperones with important functions in protein folding and in signal transduction. The HSP90 protein structure is so well conserved that some HSP90 antibodies are reactive with a broad range of species from humans to chickens (1). In humans there are 17 known genes encoding the HSP90 family members. The HSP90 family consists of 4 different classes: HSP90AA, HSP90AB, HSP90B, and TRAP.

Integrins are a large family of trasmembrane proteins involved in cell adhesion and form a link between the intracellular cyskeletal proteins and extracellular matrix proteins. Integrins exist as heterodimers consisting of alpha and beta subunits. In addition to cell adhesion these integrin complexes play key roles in diverse processes such as signal transduction, cell migration, proliferation, differentiation, and apoptosis. Integrins consist of three domains: the extracellular domain, the transmembrane domain, and the cytoplasmic tail.

CD45, also known as T200 or the Leukocyte Common Antigen (LCA), is encoded by the Protein Tyrosine Phosphatase Receptor type C (PTPRC) gene. The protein is expressed exclusively on cells of the haematopoietic system, and is one of the most abundant leukocyte cell surface glycoproteins (1). Different isoforms of CD45 are found on specific lymphocyte sub-populations, and are generated by alternative splicing. (2). At least four variants of the human protein can be distinguished by electrophoresis, with molecular weights ranging from 180-220kDa (3).

NOX4 is an NADPH oxidase that generates superoxide within the cell. It is primarily found in vascular cells, fibroblasts, and osteoclasts, with abundant expression in the kidney. Unlike its family members NOX1 and NOX2, NOX4 is constitutively active, producing primarily H2O2 rather than O2. This different species generated triggers NOX4-specific actions in downstream cell signaling.