Abstract
PDZ domain‐containing proteins (PDZ proteins) act as scaffolds for protein–protein interactions and are crucial for a variety of signal transduction processes. However, the role of PDZ proteins in organismal lifespan and aging remains poorly understood. Here, we demonstrate that KIN‐4, a PDZ domain‐containing microtubule‐associated serine‐threonine (MAST) protein kinase, is a key longevity factor acting through binding PTEN phosphatase in Caenorhabditis elegans. Through a targeted genetic screen for PDZ proteins, we find that kin‐4 is required for the long lifespan of daf‐2/insulin/IGF‐1 receptor mutants. We then show that neurons are crucial tissues for the longevity‐promoting role of kin‐4. We find that the PDZ domain of KIN‐4 binds PTEN, a key factor for the longevity of daf‐2 mutants. Moreover, the interaction between KIN‐4 and PTEN is essential for the extended lifespan of daf‐2 mutants. As many aspects of lifespan regulation in C. elegans are evolutionarily conserved, MAST family kinases may regulate aging and/or age‐related diseases in mammals through their interaction with PTEN.
Highlights
Insulin/IGF‐1 signaling (IIS) is an evolutionarily conserved signaling pathway that regulates organismal lifespan
Through a large‐scale yeast two‐hybrid screen and subsequent protein–protein binding assays, we found that DAF‐18/PTEN bound to the PDZ domain of KIN‐4 through its C‐terminus
We found that RNA interference (RNAi) targeting kin‐4, which encodes a microtubule‐associated serine‐threonine (MAST) family kinase (Manning, 2005), or gipc‐1 and gipc‐2, which encode GAIP‐interacting protein C proteins (Vartiainen, Pehkonen, Lakso, Nass, & Wong, 2006), had greater lifespan‐shortening effects on daf‐2 mutants than on control animals (Figure 1a–c)
Summary
Insulin/IGF‐1 signaling (IIS) is an evolutionarily conserved signaling pathway that regulates organismal lifespan. MAST kinases bind to various proteins, including microtubules (Walden & Cowan, 1993), β2‐syntrophin (Lumeng et al, 1999), TNF receptor‐ associated factor 6 (TRAF6) (Xiong, Li, Chen, Zhao, & Unkeless, 2004), cAMP‐regulated phospho‐protein (ARPP‐16) (Andrade et al, 2017), and PTEN (Valiente et al, 2005). Despite these findings, the role of MAST kinases in organismal aging remains unknown.
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