Predominant Role of mTOR Signaling in Skin Diseases with Therapeutic Potential

Abstract

The serine/threonine kinase mechanistic target of rapamycin (mTOR) plays a pivotal role in the regulation of cell proliferation, survival, and motility in response to availability of energy and nutrients as well as mitogens. The mTOR signaling axis regulates important biological processes, including cellular growth, metabolism, and survival in many tissues. In the skin, dysregulation of PI3K/AKT/mTOR pathway may lead to severe pathological conditions characterized by uncontrolled proliferation and inflammation, including skin hyperproliferative as well as malignant diseases. Herein, we provide an update on the current knowledge regarding the pathogenic implication of the mTOR pathway in skin diseases with inflammatory features (such as psoriasis, atopic dermatitis, pemphigus, and acne) and malignant characteristics (such as cutaneous T cell lymphoma and melanoma) while we critically discuss current and future perspectives for therapeutic targeting of mTOR axis in clinical practice.

Keywords: acne; atopic dermatitis; cutaneous T cell lymphoma; inhibitors; mTOR signaling pathway; melanoma; pemphigus; psoriasis; therapy.

Figure 1

mTOR signaling axis in normal cell physiology. Upon receptor binding by growth factors and cytokines, phosphatidylinositol 3-kinase (PI3K) is activated and in turn phosphorylates AKT. AKT can phosphorylate and inactivate the tuberous sclerosis (TSC) tumor suppressor protein complex that acts as a GTPase-activating protein (GAP) for the RAS homolog enriched in brain (Rheb) small G protein to regulate its activity. Retention of the Rheb-GTP bound form activates mTOR, which is comprised of two main complexes that are associated with diverse proteins such as RAPTOR, mLST8, PRAS40 and DEPTOR for complex I (mTORC1), and RICTOR, mLST8, DEPTOR, mSin1, and PROCTOR for complex II (mTORC2). mTORC1 phosphorylates downstream p70S6 Kinase 1 and modulates the eukaryotic initiation factor 4E-binding protein (4E-BP1), which prevents it from hindering eIF4E, and enabling 40S ribosomal subunit to be recruited to mRNAs, leading to the initiation of protein translation. p70S6K also phosphorylates ribosomal protein S6 that is also involved in translational regulation by the 40S ribosomal subunit, thus regulating several cellular processes such as cell proliferation, activation, and survival. By contrast, mTORC2 regulated by growth factors phosphorylates distinct groups of proteins, enabling the regulation of actin cytoskeleton and cell migration.

Figure 2

mTOR signaling in psoriasis. Several external stimuli (growth factors, cytokines, mechanical stress) are responsible for PI3K/AKT/mTOR overexpression and hyperactivation, which leads to activation of NF-κB inflammatory cascade and hyperproliferation, reduced epidermal differentiation, and apoptosis.

Figure 3

mTOR signaling in acne. Growth factors, insulin, and IGF-1 induce lipid synthesis by increasing SREBP-1 expression via the PI3K/Akt/FoxO1/mTORC1 pathway and the MAPK pathway. IGF-1 can also induce proinflammatory cytokine expression in sebocytes through NF-κB activation. Virulent C. acnes binds to TLR-2 and activates the NF-κB pathway to induce an inflammatory response in sebocytes. Androgens stimulate altered sebocytes differentiation through mTORC2 and by Wnt/β-catenin signaling pathway.