Salt-inducible kinase 1 regulates E-cadherin expression and intercellular junction stability

The protein kinase liver kinase B1 (LKB1) regulates cell polarity and intercellular junction stability. Also, LKB1 controls the activity of salt-inducible kinase 1 (SIK1). The role and relevance of SIK1 and its downstream effectors in linking the LKB1 signals within these processes are partially understood. We hypothesize that SIK1 may link LKB1 signals to the maintenance of epithelial junction stability by regulating E-cadherin expression. Results from our studies using a mouse lung alveolar epithelial (MLE-12) cell line or human renal proximal tubule (HK2) cell line transiently or stably lacking the expression of SIK1 (using SIK1 siRNAs or shRNAs), or with its expression abrogated (sik1(+/+) vs. sik1(-/-) mice), indicate that suppression of SIK1 (similar to 40%) increases the expression of the transcriptional re-pressors Snail2 (similar to 12-fold), Zeb1 (similar to 100%), Zeb2 (similar to 50%), and TWIST (similar to 20-fold) by activating cAMP-response element binding protein. The lack of SIK1 and activation of transcriptional repressors decreases the availability of E-cadherin (mRNA and protein expression by similar to 100 and 80%, respectively) and the stability of intercellular junctions in epithelia (decreases in transepithelial resistance). Furthermore, LKB1-mediated increases in E-cadherin expression are impaired in cells where SIK1 has been disabled. We conclude that SIK1 is a key regulator of E-cadherin expression, and thereby contributes to the stability of intercellular junctions.-Eneling, K., Brion, L., Pinto, V., Pinho, M. J., Sznajder, J. I., Mochizuki, N., Emoto, K., Soares-da-Silva, P., Bertorello, A. M. Salt-inducible kinase 1 regulates E-cadherin expression and intercellular junction stability. FASEB J. 26, 3230-3239 (2012). www.fasebj.org