Signaling stimulated by growth factors (MAPK, PKB/AKT) and cytokines (JAK- STAT)

Protein kinase B (PKB/Akt) is a serine/threonine kinase that plays a central role in the PI3K signaling pathway, drawing significant attention due to its involvement in various cellular processes. It exists in three isoforms that have both distinct and overlapping functions. Activation begins with PKB binding to PIP3 produced by PI3K, followed by phosphorylation at T308 by PDK1. Full activation requires an additional phosphorylation at S473 by either mTORC2 or DNA-PK, depending on the cellular context and stimulus. Beyond phosphorylation, PKB’s activity, localization, and function are further modulated by phosphatases and interacting proteins. The regulation of PKB is complex and highly context-dependent, influenced by isoform-specific roles, expression patterns, upstream signals, and binding partners. This intricate control enables PKB to mediate diverse physiological processes such as embryogenesis, immune cell and adipocyte development, glucose regulation, and the prevention of diseases like cancer.

náhled|350 px|Zapojení cytokinů do regulace buněčného cyklu a apoptózy Cytokines are molecules that transmits important information between cells and have an effect on the regulation of growth, cell division, diferenciaci, zánět and defense.^[1] They are also the basic regulators imunitního systémuand for some purposes, the coordinated action of several different cytokines is necessary – we call these synergistic and antagonistic interactions between cytokines cytokine network.^[2] Cytokines are found in the body either dissolved in fluid (plasma, tissue fluid) or bound to the membrane (so-called membrane forms).

Basic characteristics of cytokines[edit | edit source]

Pleiotropy: the action of cytokines on several different types of cells (např. B-lymfocyty, mastocyty),
specificity: the effect is typical only for the given cytokine,
redundancy: some cytokines can be replaced by others, e.g. IL-2 and IL-4 stimulate B-lymphocyte proliferation,
synergism: the effects of different cytokines complement each other,
antagonism: one cytokine blocks the effects of another cytokine (e.g. IFN-γ blocks the switch to IgE synthesis, which induces IL-4^[1]),
Cascade action: one cytokine induces the production of another.

náhled|450 px|Působení cytokinů The action of cytokines (given by the distance of the target structure) can be:

autocrine,
paracrine,
endocrine. (viz obrázek vpravo pro podrobnosti)

Cytokine receptors[edit | edit source]

první podjednotka slouží pro specifickou vazbu cytokinů (ukládá se extracelulárně),
druhá (a možná i třetí) slouží ke spojení s intracelulárními signálními molekulami.

Signal transduction occurs mostly through protein kinases (most often kinases of the Jak group). These kinases are non-covalently bound to the intracellular part of the receptor. After cytokine binding, the kinases come closer to each other and become activated. The activated enzymes phosphorylate other proteins and the entire cascade is triggered.

In addition to protein kinases, it is also necessary to mention G-proteins (mimochodem, v r. 2012 byla za studium G proteinů udělena Nobelova cena). Chemokine receptors (see below) are associated with G proteiny. The principle of function is different from protein kinases, but the consequences are similar: change in enzyme activity, cell cycle regulation, degranulation, etc..

Finally, there are some receptors (e.g. for FGF, EGF, TGF-β) that have a kinase domain in their cytoplasmic part (so-called receptor kinases).

The final results of signaling depend on the nature of the receptor and the interaction of other signals. They can be almost anything from stimulation proliferace, through a change in activity iontových kanálů and membrane enzymes, up to induction apoptózy.

Classification^[2][edit | edit source]

Historically, there was talk of lymphokines and monokines (molecules secreted by lymphocytes and monocytes, respectively), but this is not a very precise division and is no longer used today. Cytokines can therefore be divided into several groups:

interleukins (mainly regulate leukocytes),
chemokines (e.g. IL-8, have chemotactic activity),
interferons (component of antiviral immunity),
transforming growth factors (TGF) – TGF-α stimulates mitosis, TGF-β inhibits mitosis (structurally different molecules),
colony stimulating factors (CSF) – stimulate cell differentiation in the bone marrow,
tumour necrosis factors (TNF) – mostly induce apoptosis,
other growth factors – e.g. erytropoietin, FGF.

Classification by function[edit | edit source]

This division is only approximate, but it allows at least a rough orientation in the intricate cytokine network:

inflammation-promoting cytokines (pro-inflammatory), including chemokines: TNF, IL-1, IL-4, IL-6, IL-8, IL-12,
inflammation-inhibiting cytokines (anti-inflammatory): IL-6, IL-10, TGF-β,
cytokines with hematopoietic cell growth factor activity: IL-2, IL-3, IL-4, IL-5, C-CSF, CD70, CD30L,
cytokines involved in humoral immunity (Th2): IL-4, IL-5, IL-9, IL-10, IL-13, TGF-β,
cytokines involved in cellular immunity (Th1): IL-1, IL-2, IL-12, IL-15, IFN-γ, TNF,
cytokines with antiviral effect: IL-28, IFN-α, IFN-β, IFN-γ.