A Multisensory Network Drives Nuclear Mechanoadaptation

Abstract

Cells have adapted to mechanical forces early in evolution and have developed multiple mechanisms ensuring sensing of, and adaptation to, the diversity of forces operating outside and within organisms. The nucleus must necessarily adapt to all types of mechanical signals, as its functions are essential for virtually all cell processes, many of which are tuned by mechanical cues. To sense forces, the nucleus is physically connected with the cytoskeleton, which senses and transmits forces generated outside and inside the cell. The nuclear LINC complex bridges the cytoskeleton and the nuclear lamina to transmit mechanical information up to the chromatin. This system creates a force-sensing macromolecular complex that, however, is not sufficient to regulate all nuclear mechanoadaptation processes. Within the nucleus, additional mechanosensitive structures, including the nuclear envelope and the nuclear pore complex, function to regulate nuclear mechanoadaptation. Similarly, extra nuclear mechanosensitive systems based on plasma membrane dynamics, mechanotransduce information to the nucleus. Thus, the nucleus has the intrinsic structural components needed to receive and interpret mechanical inputs, but also rely on extra nuclear mechano-sensors that activate nuclear regulators in response to force. Thus, a network of mechanosensitive cell structures ensures that the nucleus has a tunable response to mechanical cues.

The anterior gradient homologue 2 (AGR2) co-localises with the glucose-regulated protein 78 (GRP78) in cancer stem cells, and is critical for the survival and drug resistance of recurrent glioblastoma: in situ and in vitro analyses

“…Alternatively, in a cell line with wild-type p53 , where the threshold of nuclear integrity is dependent on a functional P53, repression of AGR2 may interfere with P53, as previously shown, and cause multinucleation [ 94 , 95 ]. In contrast, in a system such as Jed41_GB, where cells grow slower, have adapted to dysfunctional genes that are important for nuclear integrity such as P53 , leukaemia NUP98 fusion partner 1 ( LNP1 ) and Sad1 and UNC84 domain containing 2 ( SUN2 ) [ 96 , 97 ], the repression of AGR2 could then directly induce apoptosis by enabling the degradation of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl2) and BCL2 Like 1(Bcl2l1), as previously seen in head and neck squamous cell carcinoma cell lines [ 98 ].…”

TGFβ treatment alters the scleral fibroblast migratory response to cyclic strain in an ERK-dependent manner

“…Cytoskeletal components link the outer cell membrane and the nucleus 23 . Through this linkage and activation of signaling molecules such as YAP, ERK, and rho-kinases, external mechanical signals can initiate alterations in nuclear shape and cellular position 24 .…”