The STK38-XPO1 axis, a new actor in physiology and cancer.

The Hippo signal transduction pathway is an essential regulator of organ size during developmental growth by controlling multiple cellular processes such as cell proliferation, cell death, differentiation, and stemness. Dysfunctional Hippo signaling pathway leads to dramatic tissue overgrowth. Here, we will briefly introduce the Hippo tumor suppressor pathway before focusing on one of its members and the unexpected twists that followed our quest of its functions in its multifarious actions beside the Hippo pathway: the STK38 kinase. In this review, we will precisely discuss the newly identified role of STK38 on regulating the nuclear export machinery by phosphorylating and activating, the major nuclear export receptor XPO1. Finally, we will phrase STK38's role on regulating the subcellular distribution of crucial cellular regulators such as Beclin1 and YAP1 with its implication in cancer.

The hippo kinase STK38 ensures functionality of XPO1.

The proper segregation of basic elements such as the compartmentalization of the genome and the shuttling of macromolecules between the nucleus and the cytoplasm is a crucial mechanism for homeostasis maintenance in eukaryotic cells. XPO1 (Exportin 1) is the major nuclear export receptor and is required for the export of proteins and RNAs out of the nucleus. STK38 (also known as NDR1) is a Hippo pathway serine/threonine kinase with multifarious functions in normal and cancer cells. In this review, we summarize the history of the discovery of the nucleo/cytoplasmic shuttling of proteins and focus on the major actor of nuclear export: XPO1. After describing the molecular events required for XPO1-mediated nuclear export of proteins, we introduce the Hippo pathway STK38 kinase, synthetize its regulation mechanisms as well as its biological functions in both normal and cancer cells, and finally its intersection with XPO1 biology. We discuss the recently identified mechanism of XPO1 activation by phosphorylation of XPO1_S1055 by STK38 and contextualize this finding according to the biological functions previously reported for both XPO1 and STK38, including the second identity of STK38 as an autophagy regulator. Finally, we phrase this newly identified activation mechanism into the general nuclear export machinery and examine the possible outcomes of nuclear export inhibition in cancer treatment.

STK38 kinase acts as XPO1 gatekeeper regulating the nuclear export of autophagy proteins and other cargoes.

STK38 (also known as NDR1) is a Hippo pathway serine/threonine protein kinase with multifarious functions in normal and cancer cells. Using a context-dependent proximity-labeling assay, we identify more than 250 partners of STK38 and find that STK38 modulates its partnership depending on the cellular context by increasing its association with cytoplasmic proteins upon nutrient starvation-induced autophagy and with nuclear ones during ECM detachment. We show that STK38 shuttles between the nucleus and the cytoplasm and that its nuclear exit depends on both XPO1 (aka exportin-1, CRM1) and STK38 kinase activity. We further uncover that STK38 modulates XPO1 export activity by phosphorylating XPO1 on serine 1055, thus regulating its own nuclear exit. We expand our model to other cellular contexts by discovering that XPO1 phosphorylation by STK38 regulates also the nuclear exit of Beclin1 and YAP1, key regulator of autophagy and transcriptional effector, respectively. Collectively, our results reveal STK38 as an activator of XPO1, behaving as a gatekeeper of nuclear export. These observations establish a novel mechanism of XPO1-dependent cargo export regulation by phosphorylation of XPO1's C-terminal auto-inhibitory domain.