PROTEIN KINASES AND SIGNAL TRANSDUCTION

RESEARCH ARTICLES

The activity of a cell, be it cell division or the production and secretion of molecules such as enzymes, hormones, or cytokines, are regulated, i.e., a cell will divide or synthesize other molecules only in response to specific signals. These signals are induced within the cell by the binding of a molecule, usually a protein, to another molecule, also a protein, on the surface of a cell. The former molecule is called a ligand; the latter a cell surface receptor.

For the immune response, important ligands are antigens and cytokines. Antigens will bind Ig molecules on B-cells, the TCR, Fc receptors (binds C2 region of Ig heavy chain), and MHC molecules, while cytokine will bind to their specific receptor.

This ligand/receptor interaction or binding initiates a process within the cell called signal transduction that starts, on the cytoplasmic side of the receptor (the cytoplasmic tail of the receptor), with the phosphorylation of tyrosine, serine, or threonine residues on the receptor by protein tyrosine kinases (PTK) or serine/threonine protein kinases and ends with DNA transcription of the target gene induced by DNA transcriptional factors. The cytoplasmic tail of the receptor (Ig alpha/Ig beta of membrane IgM and IgD, CD3 molecule, the zeta and eta chain of the TCR, and some Fc receptors) may have a sequence called immunoreceptor tyrosine-based activation motif (ITAM). The tyrosine residues within this motif are phosphorylated by src and syk family PTK. Once the DNA is transcribed, protein ( enzymes, hormones, cytokines etc.) is produced.

PTK's that are involved in signal transduction include:

• src (CD4, CD8, and CD3 molecules) family of protein tyrosine kinases (src, yes, fgr, fyn, lck, hck, and blk),
• syk (B-cell and T-cell receptors) and ZAP-70 (T-cell and NK cell receptors) family of protein tyrosine kinases, and
• jaks (cytokine receptors) family of protein tyrosine kinases (tyk-2, jak1, jak-2, and jak-3. In addition to the phosphorylation of tyrosine residues, these enzymes have regions called src-homology-2 (SH2) and SH3 domains that permit binding interactions with other proteins such as Signal Transducer and Activator of Transcription Proteins (STAT). STAT's are involved in the initial stages of signal transduction as well as DNA transcription of cytokine genes. Other transcriptional factors involved include AP-1, NF-kB, Oct-1, and NFAT.

Thus, a generalized signal transduction pathway would involve:

1. ligand/receptor binding,
2. PTK phosphorylation of the receptor cytoplasmic tail, GTP-binding proteins, and transcriptional factors; increase of intracellular Ca++ concentration,
3. binding of transcriptional factors to DNA regulatory sequences, and
4. expression of protein.

A number of signaling pathway may be activated upon ligand/receptor binding involving several DNA transcriptional factors and target DNA sequences.