Kinesin Adapter JLP Links PIKfyve to Microtubule-based Endosome-to-Trans-Golgi Network Traffic of Furin

Abstract

In mammalian cells, the endosomal/endocytic system comprises an interconnected and morphologically complex network of membrane organelles that supports fundamental functions such as nutrient entry and delivery for degradation, removal and degradation of plasma membrane or Golgi proteins, regulation and integration of signaling pathways, and protein recycling to the cell surface or the TGN 2 (1-4). From the plasma membrane, the endocytosed cargo is first delivered to early endosomes/sorting endosomes. Cargoes destined for recycling to the cell surface then enter the endocytic recycling compartment, whereas others, intended for degradation, remain in early endosomes. Early endosomes undergo a series of changes, known as maturation, to give rise to maturing transport intermediates (herein ECV/MVBs; also Ref. 5) and to late endosomes that fuse with lysosomes to deliver cargo for degradation. Recycling or degradation is not the only outcome of the cell surface-originated cargoes. A set of internalized transmembrane proteins, including intracellular sorting receptors, enzymes, and toxins, are retrieved from the endosomal system and transported to the TGN. The endosome-to-TGN trafficking of the acid-hydrolase-sorting receptor, CI-MPR, the endopeptidase furin, and the putative cargo receptor TGN38 are the best studied examples. These cargoes are highly enriched in the TGN at steady state but arrive there from different compartments, utilizing distinct mechanisms. Thus, TGN38 enters the TGN from the endocytic recycling compartment by an iterative removal from the latter compartment, furin reaches the TGN by exiting the early/late endosomal system, and CI-MPR implements features of both pathways (4, 6 -9).Whereas the detailed molecular and cellular mechanisms underlying the membrane progression in the course of cargo transport through the endosomal system or retrieval from early/late endosomes to the TGN is still elusive, experimental evidence has been accumulating to implicate PIKfyve, the sole enzyme for PtdIns(3,5)P 2 synthesis (10). Thus, PIKfyve has been found to interact with the late endosome-to-TGN transport factor Rab9 effector p40 (11). Furthermore, disruption of the PtdIns(3,5)P 2 homeostatic mechanism by means of expres-

Cdo Binds Abl To Promote p38α/β Mitogen-Activated Protein Kinase Activity and Myogenic Differentiation

“…Therefore, C2C12 cells depleted of Abl by RNAi had a diminished capacity to activate p38 MAPK in response to differentiation-inducing culture conditions. p38 activation during myogenic differentiation in vitro is substantially, though not completely, dependent on Cdo/ Bnip-2 signaling, but stress-mediated activation of p38 in myoblasts is independent of Cdo and Bnip-2 (19). As Abl is implicated in stress responses (46), we asked whether p38 activation in C2C12 cells in response to anisomycin is dependent on Abl.…”

“…These complexes also contain JLP, a scaffold protein for the p38 MAPK pathway that also binds several other signaling molecules in various contexts (e.g., the phosphatidylinositol 5-kinase PIKfyve, G ␣13 , and kinesin light chain 1) (19,26,27,32). We therefore asked whether Abl and JLP associate.…”

Lysosome enlargement during inhibition of the lipid kinase PIKfyve proceeds through lysosome coalescence

“…http://dx.doi.org/10.1101/295246 doi: bioRxiv preprint first posted online Apr. 5, 2018; targeting lysosomal proteins to lysosomes (Ikonomov et al, 2009a;Rutherford et al, 2006;Min et al, 2014). Given this, we suspected that TFEB activation may not contribute to lysosome swelling in cells acutely suppressed for PIKfyve.…”

“…The decoupling between enhanced transcription and constant protein levels may result from pleiotropic effects of PIKfyve inhibition. For example, PIKfyve is known to govern trafficking of newly synthesized lysosomal genes by controlling recycling of mannose-6-phosphate receptors (Gayle et al, 2017;Ikonomov et al, 2009a;Rutherford et al, 2006;Zhang et al, 2007). By contrast, cells chronically impaired for PIKfyve have augmented LAMP1 levels (Ferguson et al, 2009(Ferguson et al, , 2010.…”

Scaffold Protein JLP Is Critical for CD40 Signaling in B Lymphocytes

“…Several members of the JIP family have been discovered: JIP1-4 and JNK-associated leucine zipper protein (JLP), which assemble various components in the JNK and p38 signaling pathways (2). Aside from roles in the control of signaling flow, the JLP scaffold protein is also involved in intracellular molecular trafficking or vesicle transportation (3). JLP has been documented, along with other JIPs, to be important in vesicle or protein transport via its association with the motor protein kinesin or dynein, which is generally required for anterograde or retrograde transport of cargo between the cell center and periphery along microtubules (4,5).…”