New insights into growth hormone action

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Somatic growth promotion by pituitary extracts was noted 75 years ago.
• The molecular mechanisms underlying growth hormone (GH) action have been elucidated in the last two decades.
• Key discoveries include the GH receptor, Janus kinase 2 (JAK2), and signal transducer and activator of transcription 5 (STAT5).

Purpose of the Study:

• To review the molecular basis of GH action on postnatal growth.
• To present a new model for GH receptor activation.
• To investigate the role of STAT5 in postnatal growth using genetically modified mice.

Main Methods:

• Cloning of the GH receptor.
• Identification of JAK2 as the receptor-associated tyrosine kinase.
• Delineation of STAT5a/b as key transcription factors.
• Analysis of mouse models with targeted knockins to the GH receptor cytoplasmic domain.
• Examination of hepatic transcript profiles in these mouse models.

Main Results:

• A model of GH receptor activation involving subunit rotation within a constitutive dimer is proposed.
• Mice with targeted knockins to the GH receptor cytoplasmic domain exhibit specific phenotypes.
• Hepatic transcript profiles reveal significant alterations in these mouse models.
• STAT5a/b activation by JAK2 is central to GH-mediated postnatal growth.

Conclusions:

• The interaction between GH receptor, JAK2, and STAT5 is fundamental for postnatal growth.
• STAT5 plays a critical role in mediating the effects of GH on somatic growth.
• The proposed model provides new insights into GH receptor signaling.