Signal Transduction across the Nuclear Envelope: Role of the LINC Complex in Bidirectional Signaling

Abstract

The primary functions of the nuclear envelope are to isolate the nucleoplasm and its contents from the cytoplasm as well as maintain the spatial and structural integrity of the nucleus. The nuclear envelope also plays a role in the transfer of various molecules and signals to and from the nucleus. To reach the nucleus, an extracellular signal must be transmitted across three biological membranes: the plasma membrane, as well as the inner and outer nuclear membranes. While signal transduction across the plasma membrane is well characterized, signal transduction across the nuclear envelope, which is essential for cellular functions such as transcriptional regulation and cell cycle progression, remains poorly understood. As a physical entity, the nuclear envelope, which contains more than 100 proteins, functions as a binding scaffold for both the cytoskeleton and the nucleoskeleton, and acts in mechanotransduction by relaying extracellular signals to the nucleus. Recent results show that the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which is a conserved molecular bridge that spans the nuclear envelope and connects the nucleoskeleton and cytoskeleton, is also capable of transmitting information bidirectionally between the nucleus and the cytoplasm. This short review discusses bidirectional signal transduction across the nuclear envelope, with a particular focus on mechanotransduction.

Keywords: KASH protein; LINC complex; SUN protein; mechanotransduction; nuclear envelope.

Figure 1

A model of Linker of Nucleoskeleton and Cytoskeleton (LINC) complex-mediated inside-out and outside-in signaling pathways. An enormous number of signaling pathways are integrated within cells. Outside-in signaling pathways, which originate within the cytoplasm or extracellular environment and terminate within the nucleus, can be roughly categorized into two groups. In the first pathway, mechanical stimuli are directly transferred to the nucleus via the LINC complex. The second pathway utilizes transcription factors such as Yes-associated protein (YAP) and megakaryoblastic leukemia 1 (MKL1) that shuttle between the cytoplasm and the nucleus through the nuclear pore complex (NPC). More importantly, the nucleus also plays a role as an information submission source. Inside-out signaling results in the transfer of signals from the nucleoplasm to the cytoplasm across the nuclear envelope (NE). SUN domain: Sad1/UNC-84.