Novel roles for mucin 1 in the kidney

Abstract

Purpose of review: Recent studies in the kidney have revealed that the well characterized tumor antigen mucin 1 (MUC1/Muc1) also has numerous functions in the normal and injured kidney.

Recent findings: Mucin 1 is a transmembrane mucin with a robust glycan-dependent apical targeting signal and efficient recycling from endosomes. It was recently reported that the TRPV5 calcium channel is stabilized on the cell surface by galectin-dependent cross-linking to mucin 1, providing a novel mechanism for regulation of ion channels and normal electrolyte balance.Our recent studies in mice show that Muc 1 is induced after ischemia, stabilizing hypoxia-inducible factor 1 (HIF-1)α and β-catenin levels, and transactivating the HIF-1 and β-catenin protective pathways. However, prolonged induction of either pathway in the injured kidney can proceed from apparent full recovery to chronic kidney disease. A very recent report indicates that aberrant activation of mucin 1 signaling after ischemic injury in mice and humans is associated with development of chronic kidney disease and fibrosis. A frameshift mutation in MUC1 was recently identified as the genetic lesion causing medullary cystic kidney disease type 1, now appropriately renamed MUC1 Kidney Disease.

Summary: Studies of mucin 1 in the kidney now reveal significant functions for the extracellular mucin-like domain and signaling through the cytoplasmic tail.

Figure 1. Mucin 1 structure and functional domains

Mucin 1 is a type 1 transmembrane protein with a cleaved signal sequence and cytoplasmic C-terminus. The extracellular domain includes a SEA (sea urchin sperm protein, enterokinase and agrin) module with five N-linked glycans that exhibits autocatalytic cleavage yielding a heterodimeric structure (dashed line). The large mucin-like subunit also includes a variable number of tandem repeats (VNTR) that are rich in Pro and O-glycosylated Ser and Thr residues. The smaller subunit includes the transmembrane domain and cytoplasmic tail detailed in Figure 2. Functions attributed to each domain are noted with details in the text.

Figure 2. Functional activities of the mucin 1 cytoplasmic tail

The 72-residue cytoplasmic domain is numbered from the transmembrane domain due to the extracellular VNTR. MUC1 binding of Grb2 at pY⁶⁰TNP and the clathrin adaptor AP-2 at Y²⁰HPM is required for endocytosis, while binding of clathrin adaptor AP-1 at Y²⁰HPM and dual palmitoylation of the CQC³ motif is required for recycling from endosomes back to the cell surface [13,14]. Mucin dimerization through the CQC³ motif yields a nuclear targeting signal based on the adjacent RRK [16]. Peptides based on the CQCRRK motif can block MUC1 activities in the nucleus [67]. The site of IKKβ interaction is indicated which initiates NF-kB activation [68]. β-catenin binding to a canonical SXXXXXSSLS⁵⁹ site is(i) enhanced by PKC5 phosphorylatin of Thr⁴¹ and Tyr⁴⁶ phosphorylation by either the EGF receptor or Src family kinases, and (ii) blocked by Ser⁴⁴ phosphorylation by GSK3p that binds at SXXXS⁴⁴ (for review, see [1-3]).

Figure 3. Mucin 1 is expressed in the proximal tubule during ischemia-reperfusion injury

Mice were subjected to 19 min ischemia and recovery for t=0 or 3 days. Kidneys were fixed in PFA, embedded in paraffin, subjected to antigen retrieval, and incubated with rabbit anti-OAT1 (organic anion transporter 1) antibodies (red) to label the basolateral surface of the proximal tubule cells (PT), and with Armenian hamster CT-2 anti-MUC1 cytoplasmic tail antibodies (green). Nuclei were stained blue. Muc1 appears on the apical surface of flatten cells in the recovering proximal tubule at 3 d recovery (yellow arrows). Glomeruli (G) are also indicated.