Edmond Fischer

Cell Signaling in Health and Disease


Abstract

Protein phosphorylation can be considered the most prevalent mechanism by which eukaryotic cellular events are regulated, and phosphorylation of tyrosine residues in proteins has been directly implicated in the regulation of cell growth, differentiation and transformation. Mitogenic hormones and growth factors act on receptors that are tyrosine kinases; their signal is transduced by a variety of adapter or docking proteins interacting with one another through different binding modules (SH2, SH3, PH, WW, PDZ, etc.) thereby initiating many diverse signaling pathways. Mutations in these receptors can lead to a number of pathological conditions such as hypopigmentation, achondroplastic dwarfism, non-insulin-dependent diabetes or oncogenicity.

Of course, regulation must also involve protein tyrosine phosphatases (PTPs), an expanding family of transmembrane and intracellular enzymes that catalyze the reverse reaction. Most receptor forms contain two cytoplasmic catalytic domains and highly variable external stuctures often containing immunoglobulin-like and/or fibronectin III repeats. Surprisingly, they display all the hallmarks of cell adhesion molecules. This would suggest that they are involved in - or are regulated by - cell-cell interaction with the very exciting possibility that they might be directly implicated in contact inhibition. The functional properties of some of these receptors will be discussed, including those of: a) the leukocyte common antigen CD45, which participates prominently in T- and B-cell signaling, acting presumably through the activation of src family tyrosine kinases such as lck, fyn or lyn; and b) receptors who have a carbonic anhydrase-like motif at their N-terminus and whose ligand has recently been identified as contactin: they are presumed to play a prominent role in embryonic neural development.

Likewise, the intracellular PTPs display a great diversity of regulatory/localization segments, preceding or following conserved catalytic domains. The properties a human T-cell enzyme as compared to a truncated form in which the regulatory/localization segment has been deleted, will be discussed. The data indicate that kinases and phosphatases cannot be viewed as simply providing opposing "on/off" signals: depending on their structure and where they localize within the cells, tyrosine phosphatases can act either positively or negatively in eliciting a particular physiological response.


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