Networking Between γc and GH-R Signaling in the Control of Cell Growth

Rosa      Romano; Loredana      Palamaro; Giancarlo      Parenti; Mariacarolina      Salerno; Anna      Fusco; Pietro      Vajro; Donatella      Capalbo; Brigida      Ranieri; Roberta      Naddei; Claudio      Pignata

Abstract

The family of type I cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, shares common transducing element the common cytokine receptor γc. The receptors containing γc exert prominent mitogenic effects and play an important role in several immunological functions and in supporting cell survival. The γc-dependent cytokine receptors use the Janus Kinase (JAK)/Signal transducer and activator of transcription (STAT) signaling pathway to mediate gene activation or repression. The Growth Hormone (GH) is a peptide of 191 amino acids and 22 kDa molecular weight, produced by the adenohypophysis, that regulates many important functions, as control of cellular metabolism, immune functions, fertility and somatic growth. Of note, the existence of a previously unappreciated functional interaction between γc and Growth Hormone receptor (GH-R) has been recently documented. The impairment of various GHinduced events in patients affected with severe combined immunodeficiencies due to γc defects suggests a potential functional interaction between GH-R pathways and γc, indicating a further link between endocrine and immune system with potential implication of the molecule in the cell cycle progression and control. GH-R pathways and γc interaction leads to the activation and intranuclear translocation of STAT5b protein. Moreover, evidence suggests that both GHinduced and spontaneous cell cycle progression and cell growth are strongly dependent on the amount of γc expression. To date, the regulation of cell survival and apoptosis can be considered a delicate teamwork and a proper functionality of γc-dependent cytokines on the whole seems to play prominent roles, as revealed by the profound impact that their abnormal function can have on the homeostasis of the immune system.

Keywords: Cell growth, γc, GH, GH-R, JAKs, STATs, Cytokines, Combined Immunod eficiency (X-SCID)