Protein import, nucleus pathway

An intensely investigated trophic factor is IGF-I, a pleiotropic protein important for normal development and maintenance of central and peripheral nervous system tissues. It interacts with the tyrosine kinase IGF-IR consisting of two extracellular a-subunits linked via disulfide bonds and two P-subunits, which are largely cytoplasmic and contain the tyrosine kinase domains. When activated by its substrate, IGF-I the IGF-IR signals to its major substrates, i.e., insulin receptor substrate-1 and -2 (IRS-1, IRS-2) and to She and from there on via the Ras/Raf pathway, via MEK and MAPK to the nucleus (Rubin and Baserga,... 

Disorders affecting the import pathways to mitochondria, peroxisomes, and the nucleus (e.g., mutations in the peroxisomal Pex proteins leading to Zellweger syndrome). 

In comparison to signaling pathways which utilize transmembrane receptors (see chapter 5, 8,11), signahng via nuclear receptors is of relatively simple structure. The pathways lead directly, with only a few participating protein components, from the extracellular space to the level of the DNA in the nucleus. Most important protein components of the signal pathway are known and well characterized. Nevertheless, we understand very little of the mechanism by which the activated receptors lead to a transcription initiation. This is due to the extreme complexity of transcription initiation in eucaryotes (see 1.2). Both the variety of proteins involved in the formation of a competent initiation complex, as well as the influence of chromatin structure, make it difficult to elucidate the exact function of nuclear receptors in transcription initiation. 

An important target protein of Ptdlns(3,4,5)P3 is Akt kinase, also known as protein kinase B (PKB). The signahng pathway for Akt kinase shown in Fig. 6.9b illustrates the role of P13-kinase and Ptdlns(3,4,5)P3 in growth factor controlled signal pathways that lead from the cell membrane into the cytosol and the nucleus. 

When AIF and endonuclease G are released into the cytoplasm, they directly translocate to the nucleus and induce DNA fragmentation and subsequent chromosomal condensation, a remarkable morphological feature of the apoptotic process. AIF induces chromatin digestion into large fragments of approximately 50 kb, probably by activating a nuclear DNAse. Therefore, these proteins are important for the caspase-indepen-dent apoptosis pathway. 

---