**15. The new view of cellular compartments**

Another noteworthy aspect is that the cellular compartments are currently the object of many discussions in experimental biology, and we are witnessing a reconceptualization of these compartments, which involves the way they are structured and work, as well as their possible relationships with disease development at the cellular level.

It is logical to think that since a cell is in a process of constant division, for any given cell division, the elements in the nucleus and the cytoplasm are mixed, and at this important moment for cellular functioning, the cytoplasmic and nuclear components share the same general compartment that is the cytoplasm of the cell under division. According to this view, there is a very tenuous separation between the cytoplasm and the nucleus of a cell, and the sub compartments generated inside the cytoplasm are what really matters in a cell. Although many scenarios of the separation of specific functions have been detected inside the nucleus (Zhao et al., 2009; Spector & Lamond, 2011), none of these microenvironments would be maintained in cells in the process of cell division.

These new sub compartments that are important for the understanding of the mechanisms of diseases such as cancer are the networks of endocytic membrane represented by a system of interconnected membranous organelles and endosomes that are responsible for the selection of destination and transport of various types of macromolecules from the extracellular milieu into the cell and within the cell. A recent discovery reveals that the process of endocytosis and endosomes would be crucial for the maintenance of cellular homeostasis, ensuring the compartmentalization of transduction processes of intracellular signals (Scita & Di Fiore, 2010). It is now widely accepted that systems of endocytic membrane trafficking and intracellular signaling are closely interconnected and endosomes could act as signaling platforms (Hupalowska & Miaczynska, 2011).

The main endosomal compartment that regulates intracellular signaling processes would be the so-called multivesicular bodies (MVB). It would have a specific role in the sequestration of receptors activated in the membrane that by means of an intracellular mechanism of endocytosis would be placed inside the lumen of the MVB, unable to access the components of intracellular signaling, which would reduce and negatively regulate the signaling pathway of these receptors (Katzmann et al., 2002; Raiborg & Stenmark, 2009).

Surprisingly, this compartment can also play a role in positive regulation of certain signaling pathways through sequestration of inhibitors (Taelman et al., 2010). Because of its important role in cancer, it is worth mentioning that the Gsk3 and CK1 promoted by the Wnt signaling pathways would be hidden in internal vesicles inside the MVB. The protein complexes involving the Wnt receptor, Gsk3 and CK1 (among others), are then taken inside the lumen of the MVB, separating Gsk3 from their cytoplasmic substrates (Figure 1h). Consequently, in the absence of Gsk3, which is now inside the MVB, β-catenin would be stabilized in the cytoplasm, translocate into the nucleus and activate transcription.

The endosomal compartments are, thus, a trapping mechanism of enzyme and receptors, and it is believed that it produces the stabilization of many cellular proteins. Coincidentally, as discussed in the chapter, proteins as connexin and Kaiso, which are essential for the diagnosis and prognosis of cancer, are always accumulated in the cytoplasm in cancer cells.

This knowledge of endosomal compartments can be of paramount importance for the understanding of the molecular mechanisms by which diseases such as cancer initiate. For example, in the case of specific connexins, the tumor suppressor role could be related to the sequestration of these proteins in MVB during the onset of this tumor. Other related studies have proposed connexins as platforms for sequestering signaling proteins, suggesting that connexins might directly sequester MAPK (Mitogen-Activated Protein Kinase), CDK (Cyclin-dependent kinase), and Src (Proto-oncogene tyrosine-protein kinase) by SH2 and SH3 domains of the carboxyl terminal tail of Cx43 and, thus, act as a tumor suppressor (Cofre & Bermudez, 2011).

No studies have shown the association of connexins and endosomal compartments, and yet such studies could help understand the controversy of the expression of connexins in the plasma membrane during early metastasis, which can be related to deregulation mechanisms of cellular physiology of the endocytic compartment.
