CIB1: a small protein with big ambitions

Abstract

Calcium- and integrin-binding protein 1 (CIB1) is a small, ubiquitously expressed protein that was first identified as an intracellular binding partner of a platelet-specific α-integrin cytoplasmic tail. Although early studies revealed a role for CIB1 in regulating platelet integrin activity, recent studies have indicated a more diverse role for CIB1 in many different cell types and processes, including calcium signaling, migration, adhesion, proliferation, and survival. Increasing evidence also points to a novel role for CIB1 in cancer and cardiovascular disease. In addition, an array of CIB1 binding partners has been identified that provide important insight into how CIB1 may regulate these processes. Some of these binding partners include the serine/threonine kinases, p21-activated kinase 1 (PAK1), apoptosis signal-regulating kinase 1 (ASK1), and polo-like kinase 3 (PLK3). Structural and mutational studies indicate that CIB1 binds most or all of its partners via a well-defined hydrophobic cleft. Although CIB1 itself lacks known enzymatic activity, it supports the PI3K/AKT and MEK/ERK oncogenic signaling pathways, in part, by directly modulating enzymes in these pathways. In this review, we discuss our current understanding of CIB1 and key questions regarding structure and function and how this seemingly diminutive protein impacts important signaling pathways and cellular processes in human health and disease.-Leisner, T. M., Freeman, T. C., Black, J. L., Parise, L. V. CIB1: a small protein with big ambitions.

Integrin αIIbβ3 outside-in signaling

“…90 The finding that CIB1 also binds to other a subunits suggests it may play a more general role in integrin function. 86 …”

The Emerging Roles of CIB1 in Cancer

“…Of note, CIB1 is also reported to inhibit the IP 3 R-Ca 2+ release channel [32]. Binding of CIB1 to the N-terminal region of IP 3 R is reduced at low free [Ca 2+ ] and could be inhibited by mutations to EF hand-III or EF hand-IV, suggesting that Ca 2+ -binding is the trigger for the CIB1-IP 3 R interaction [7]. CIB1 interact with the intracellular C-terminal domain of rat sweet taste 1 receptor member 2 (TAS1R2) also reported to inhibit IP 3 R-Ca 2+ release [4].…”

“…CIB1 is also involved in tumor metastasis by effecting tumor cell migration and spreading [7]. Until now, multiple studies have indicated that CIB1 serve important roles in regulating platelet integrin activity, cell adhesion and migration by interacting with at least six binding partners, including αIIbβ3, the coagulation factor VIII (FVIII), Wiskot-Aldrich syndrome protein (WASP), the small GTPase Rac3, P21-activatd kinases 1 (PAK1) and focal adhesion kinase (FAK).…”

“…CIB1 is a versatile protein by interacting with more than 35 binding partners so far [7]. Of interest, CIB1 is involved in embryogenesis, neural development, AD etc.…”

“…Studies suggested that Mg 2+ -CIB1 and Ca 2+ -CIB1 exhibit a more ordered 4-EF-hand structure with smaller hydrodynamic radius than a highly flexible molten globule-like CIB1 (not bound to any metals)[6, 8]. A consensus sequence 5’-MGXXXS/T-3’ at the CIB1 N terminus appears to be crucial for its myristoylation modification and plasma membrane localization [4, 7, 13, 14]. The myristoylation at the CIB1 N terminus might interfere with CIB1 cellular function [13, 15-17].…”