Endocytosis, signaling, and beyond

Abstract

The endocytic network comprises a vast and intricate system of membrane-delimited cell entry and cargo sorting routes running between biochemically and functionally distinct intracellular compartments. The endocytic network caters to the organization and redistribution of diverse subcellular components, and mediates appropriate shuttling and processing of materials acquired from neighboring cells or the extracellular milieu. Such trafficking logistics, despite their importance, represent only one facet of endocytic function. The endocytic network also plays a key role in organizing, mediating, and regulating cellular signal transduction events. Conversely, cellular signaling processes tightly control the endocytic pathway at different steps. The present article provides a perspective on the intimate relationships that exist between particular endocytic and cellular signaling processes in mammalian cells, within the context of understanding the impact of this nexus on integrated physiology.

Figure 1.

Transcriptional programs controlling endocytosis. Lysosomal stress (A) and/or starvation (B) cause nuclear translocation of the TFEB transcription factor, which binds to the E-box sequence on promoters and induces transcription of a cluster of genes (the “CLEAR network”) involved in lysosomal biogenesis/function and autophagy genes, promoting cellular clearance of nondegraded molecules. (C) Activation of HIF1 during hypoxia causes the inhibition of the RABAPTIN-5 gene transcription, inhibition of Rab5 GTP-loading and, consequently, endosomal retention of the EGFR, eventually leading to sustained EGFR signaling from the endosomal station and tumor progression. (D) On different types of cellular stresses, p53 translocates into the nucleus and activates the transcription of genes that play roles at different stations of the endocytic pathway: autophagy genes (e.g., lysosome/autophagosome components), genes involved in exosome release from MVBs (e.g., ESCRT components), and the CAV-1 gene, which stimulates caveolar endocytosis. (E) TP53 mutations found in human cancers exert part of their oncogenic potential through the P63-dependent (transcriptional-dependent) stimulation of RCP-mediated recycling of integrin-EGFR complexes, leading to induced migration and metastasis. The molecular mechanism for this remains unclear.

Figure 2.

Endocytosis modifies GPCR signaling and vice versa. (A) Activation of the β2-adrenergic receptor by catecholamine stimulates adenylyl cyclase through coupling to the heterotrimeric G protein Gs, thereby increasing the cAMP concentration in the cytoplasm. Receptor activation also initiates a process of regulated endocytosis of receptors, mediated by clathrin-coated pits, delivering activated receptors to early endosomes. (B,C) In endosomes receptors are thought to activate noncanonical signaling through the scaffold protein β-arrestin β-Arr, leading to activation of MAP kinases (B), and initiate a second “wave” of Gs-mediated activation of adenylyl cyclase that further increases cytoplasmic cAMP concentration (C). Receptors recycle to the PM by engaging a multiprotein sorting machinery, including sorting nexin 27, and the retromer complex (depicted by SNX-RM in the diagram). (D) On return to the PM, receptors couple to Gi, reducing adenylyl cyclase activity and decreasing cytoplasmic cAMP concentration. In cardiac muscle cells, this series of events causes an acute acceleration (Gs response) followed by deceleration (Gi response) of cardiac contraction (indicated by “+” and “−” arrows in figure). The GPCR-G protein system conversely regulates the endocytic process in at least two ways: (E) β-Adrenergic receptors locally prolong the surface lifetime of clathrin-coated pits that contain them, and (F) Gs acts in the early endosome membrane to promote endosome maturation through RAB5-to-7 conversion.