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J. Biol. Chem., Vol. 280, Issue 36, 31830-31840, September 9, 2005

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JAK/STAT3 Pathway Is Involved in Survival of Neurons in Response to Insulin-like Growth Factor and Negatively Regulated by Suppressor of Cytokine Signaling-3^*

Ajay Yadav, Anjana Kalita, Shivani Dhillon, and Kakoli Banerjee

From the National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi-110067, India

Janus kinases (JAK) and signal transducers and activator of transcription (STAT) proteins are activated in response to many cytokines and growth factors and are well studied in the immune system. This study was conducted to examine the role of the JAK/STAT pathway in neurons in response to tumor necrosis factor- (TNF) and insulin-like growth factor-1 (IGF-1), which play a major role during neurodegeneration, and to study their effect on expression of suppressors of cytokine signaling 3 (SOCS-3), belonging to the novel family of feedback regulators of cytokine and growth factor activities. In this report, we showed that TNF is inhibitory to the survival of primary cortical neurons at higher doses and that IGF-1 can rescue TNF-stimulated cell death. We showed that the JAK/STAT pathway is involved in this rescue as tyrphostin AG490, a specific inhibitor of JAK/STAT, completely inhibits cell survival in response to IGF-1. STAT3 gets tyrosine-phosphorylated and translocated to the nucleus in response to IGF-1. Northern blot, semi-quantitative reverse transcription-PCR, and real time PCR experiments demonstrated that the JAK/STAT pathway also up-regulated SOCS-3 mainly in response to IGF-1. SOCS-3 associated with the IGF receptor and blocked further STAT3 activation. To our knowledge, this is the first report that demonstrated the importance of the JAK/STAT pathway and the role of SOCS-3 in the survival of neurons in response to IGF-1. We have subsequently shown that SOCS-3 overexpression, on one hand, leads to neuroblastoma cell death and on the other hand leads to primary cell differentiation, indicating the involvement of SOCS-3 in cell survival and differentiation.

Received for publication, February 4, 2005 , and in revised form, June 29, 2005.

^* This work was supported by Indian Council of Medical Research and National Institute of Immunology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Staff Scientist IV, Eukaryotic Gene Expression Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi-110067, India. Tel.: 9111-26703601 Fax: 9111-26162125; E-mail: kakoli{at}nii.res.in.

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